Effect of the Buteyko Method on Resting Ventilation and Asthma Control in Asthma Patients

Monique van Oosten

Ritgerð til meistaragráðu Háskóli Íslands Læknadeild Námsbraut í Lýðheilsuvísindum Heilbrigðisvísindasvið

Áhrif Buteyko aðferðinnar á hvíldaröndun og stjórnun astmasjúkdómsins hjá astmasjúklingum

Monique van Oosten

Ritgerð til meistaragráðu í Lýðheilsuvísindum Leiðbeinandi: Marta Guðjónsdóttir Meistaranámsnefnd: Marta Guðjónsdóttir, Auðna Ágústsdóttir og Björn Magnússon

Læknadeild

Námsbraut í Lýðheilsuvísindum

Heilbrigðisvísindasvið Háskóla Íslands

Mars 2017

Effect of the Buteyko Method on Resting Ventilation and Asthma Control in Asthma Patients

Monique van Oosten

Thesis for the degree of Master of Science

Supervisor: Marta Guðjónsdóttir

Masters committee: Marta Guðjónsdóttir, Auðna Ágústsdóttir and Björn Magnússon

Faculty of Medicine

Department of Public Health

School of Health Sciences

March 2017

Ritgerð þessi er til meistaragráðu í lýðheilsufræði og er óheimilt að afrita ritgerðina á nokkurn hátt nema með leyfi rétthafa.

Prentun: Háskólaprent

Reykjavík, Ísland 2017

Ágrip

Bakgrunnur . Buteyko meðferðin (BM) virðist breyta öndun, bæta lífsgæði og astma stjórnun hjá astma sjúklingum. Rannsóknir hafa fram að þessu ekki skilgreint nægilega vel lífeðlisfræðileg áhrif meðferðarinnar.

Markmið þessarar rannsóknar er að skoða lífeðlisfræðileg áhrif BM á hvíldaröndun og stjórnun astma í hóp astmasjúklinga.

Aðferð . Í þessari framskyggnu, íhlutandi rannsókn með samanburðarhópi voru astmasjúklingar mældir þrisvar sinnum í algjörri hvíld, með 6 mánaða millibili. Þeir voru paraðir miðað við aldur, kyn og líkamsþyngdarstuðul (BMI) við heilbrigðan samanburðahóp. BM var kennd eftir fyrstu 6 mánuðina. Síðan var hópnum fylgt eftir og mældur að nýju 6 mánuðum síðar. Hvíldaröndun (öndunartíðni og andrýmd

(V T)), næmni öndunarstöðva metin út frá viljastýrðu öndunarstoppi, efnaskipti, og astma control spurningalisti (ACT) voru skoðuð. Hlutfall milli heildaröndunar (V´ E) og koltvísýringsútskilnaðar

(V´ E/V´CO 2) var reiknað út. Fráblástursgeta á einni sekúndu (FEV 1) var mæld og reiknuð sem hlutfall af hámarksandrýmd (FEV 1/FVC).

Niðurstöður : 22 (61%) af þeim 36 astmasjúklingum sem hófu rannsóknina og 20 þátttakendur í samanburðarhópi luku þátttöku. Í byrjum rannsóknarinnar voru hóparnir eins varðandi aldur, kyn og BMI, en FEV 1/FVC hlutfallið var lægra og viljastýrða öndunarstoppið styttra hjá astmahópnum (p<0.05). Eftir

BM hjá astmahópnum hafði hlutþrýstingur koltvísýrings við lok útöndunar (P ET CO 2), V´ E/V´CO 2, og stig fyrir ACT aukist (p<0.05) og viljastýrða öndunarstoppið hafði lengst (p<0.001). Eins hafði hlutþrýstingur súrefnis við lok útöndunar (P ET O2), V´ E, VT og efnaskipti minnkað en BMI hafði hækkað (p<0.05).

FEV 1/FVC var óbreytt.

Umræða : Í upphafi var hvíldaröndun svipuð hjá hópunum en næmni öndunarstöðva var meiri hjá astmahópnum. BM virðist minnka næmni öndunarstöðva þar sem viljastýrða öndunarstoppið verður lengra. Hærra P ET CO 2 og lægra P ET O2 bendir til að hlutfall milli alveolar öndunar (V´ A) og V´CO 2 (V´ A/

V´CO 2) hafi minnkað, þrátt fyrir hærra V´ E/V´CO 2. Því má álykta að lægra V T hafi aukið öndun í dauðarýminu. BM bætir stjórnun á astma án þess að hafa breytt FEV 1/FVC.

Abstract

Background : The Buteyko method (BM) seems to change breathing patterns, increase quality of life and asthma control in asthmatics. Until now, studies have not been able to identify sufficiently the physiological mechanism behind the BM.

The aim of this study is to evaluate the physiological effect of BM on resting ventilation and asthma control in an asthma group.

Methods : In this prospective, intervention study, asthmatics were measured 3 times at complete rest, at a 6-month interval. They were matched by age, gender, and body mass index (BMI) to control subjects. The first 6-month interval was the control period. The BM was taught to the asthmatics after the control period. Asthmatics were followed up and measured again after 6 months. Resting ventilation

(respiratory rate and tidal volume (VT)), respiratory chemosensitivity evaluated by breath holding time (BHT) and metabolism were assessed, and the asthma control test questionnaire (ACT) was applied.

The equivalent of pulmonary ventilation (V´ E) for carbon dioxide output (V´ E/V´CO 2) was calculated. The forced expiratory volume in one second (FEV 1) was measured and calculated as a percentage of the forced vital capacity (FEV 1/FVC).

Results : 22 (61%) of 36 asthmatics and 20 control subjects finished the study. At baseline, groups were comparable regarding age, gender and BMI. In the asthma group, FEV 1/FVC was lower and BHT was shorter (p<0.05). After BM in the asthma group, partial pressure of end-tidal carbon dioxide (P ET CO 2),

V´ E/V´CO 2, BMI and scores for the ACT had increased (p<0.05) and BHT had become longer (p<0.001).

Partial pressure of end-tidal oxygen (P ET O2), V´ E, VT and metabolism had decreased (p<0.05). FEV 1/FVC remained the same.

Discussion : At baseline, resting ventilation was alike between the groups, but respiratory chemosensitivity was higher in the asthma group as seen in shorter BHT. BM effected resting ventilation by decreasing respiratory chemosensitivity for CO 2 as evaluated by longer BHT. It could be concluded that the equivalent of alveolar ventilation (V´ A) for VĆO 2 (V´ A/VĆO 2) had decreased, evidenced by higher levels of P ET CO 2 and lower levels of P ET O2. However, V´ E/VĆO 2 had increased, implying greater dead space ventilation as a result of decreased V T. BM improved asthma control without altering

FEV 1/FVC.

Acknowledgements

First of all, I would like to express my deepest gratitude to my supervisor, Marta Guðjónsdóttir for carrying out this research project with me, and for all her guidance, support, encouragement, patience, and, most of all, her excellent teaching.

I am very grateful to my master’s committee, Auðna Ágústsdóttir and Björn Magnússon, for supporting me in this work and for sharing their expertise.

I am grateful to Reykjalundur for giving us the opportunity to perform our research in their laboratory.

Finally, I would like to thank all my family and friends for their mental support, and last, but not least, my beloved daughter Katrín Möller, for her invaluable help.

This project was financially supported by the Asthma and Allergy Foundation, the Icelandic Physiotherapy Society and the Oddur Ólafsson Foundation.

Table of contents

Ágrip ...... 3

Abstract ...... 5

Acknowledgements...... 7

Table of contents ...... 8

List of Figures ...... 10

List of tables ...... 11

List of abbreviations ...... 12

1 Introduction ...... 14

1.1 What is asthma? ...... 14 Diagnosis ...... 14 Risk factors and allergies ...... 15

1.2 Asthma control ...... 15 Control-based asthma management ...... 16 Psychological factors...... 17 Posture and physical condition ...... 17

1.3 Ventilation at rest ...... 18 The Respiratory system ...... 18 Pulmonary ventilation ...... 22 Alveolar ventilation ...... 22 Dead space ventilation ...... 23 The bicarbonate buffer system ...... 24 Spirometry...... 25 Ventilation musculature ...... 25 Breathing control ...... 26 Chemosensors ...... 28 Physiological efficient and functional ventilation...... 29 Metabolism...... 30

1.4 Asthma and resting ventilation ...... 30 Asthma and breathing therapy...... 31

1.5 The Buteyko method ...... 32 Research on BM ...... 33 Breath holding and the Buteyko method ...... 34

2 Aims and Objectives ...... 36

3 Methods ...... 37

3.1 Participants ...... 37

3.2 Protocol ...... 38 Measures ...... 39

3.3 Procedure ...... 40

3.4 Statistical analysis ...... 41

4 Results ...... 43

4.1 Ventilation ...... 43

4.2 Asthma control ...... 45

4.3 Metabolism ...... 46

4.4 Breath holding time ...... 46

5 Discussion ...... 47

5.1 Pre-intervention ...... 47

5.2 Post-intervention ...... 49

5.3 Strength and limitations ...... 51

5.4 Future studies ...... 53

6 Conclusion ...... 53

References ...... 55

Appendix A ...... 63

Appendix B ...... 64

Appendix C ...... 66

Appendix D ...... 70

Appendix E ...... 72

Appendix F ...... 73

List of Figures

Figure 1. The respiratory system...... 19

Figure 2. Airway branching in the lower respiratory tract...... 20

Figure 3. Normal bronchial tube at left side and narrowing of the bronchial tube in asthma ...... 21

Figure 4. The hemoglobine saturation curve for partial pressures of oxygen...... 22

Figure 5. Hypo- and hyperventilation ...... 23

Figure 6. The anatomic dead space...... 24

Figure 7. Spirometry, a volume-time graph...... 25

Figure 8. Muscles of breathing...... 26

Figure 9. A control system has three interconnecting components...... 27

Figure 10. Central (left-side of picture) and peripheral chemosensors (right-side) ...... 28

Figure 11. Flowchart of procedure and participants ...... 40

Figure 12. Measurements performed for both groups at M1, M2 and M3 ...... 41

Figure 13. Partial pressures of end-tidal carbon dioxide (P ET CO 2) and oxygen (P ET CO 2) ...... 44

Figure 14. Results from the ACT...... 45

Figure 15. SABA usage before and after the Buteyko method...... 45

Figure 16. Breath holding time measures ...... 46

Figure 17.∆ BHT Line Fit Plot without extreme case ...... 47

List of tables

Table 1. Potential risk factors for asthma 15 ...... 15

Table 2. Randomized control trials involving BM ...... 33

Table 3. Asthma history and medication usage at M1 ...... 38

Table 4. Measures of age, gender and BMI for all participants at M1 ...... 43

Table 5. Ventilation measurements at M1 ...... 43

Table 6. Body mass index, lung function and ventilation parameters...... 44

List of abbreviations

ANS Autonomic nerve system

APC Antigen-presenting immune cell

BHT Breath holding time

BM Buteyko Method

BTS/ACPRC guideline Guidelines for the physiotherapy management of the adult, medical, spontaneously breathing patient C3 Cervical vertebra number 3

Cl - Chloride ion

CO 2 Carbon dioxide

COPD Chronic obstructive pulmonary disease

CPG Central pattern generator

CSF Cerebral spinal fluid

DALYs Disability-adjusted life years

DB Dysfunctional breathing

DRG Doral respiratory generator

ECF Extracellular fluid

ECRHS The European Community Respiratory Health Survey I and II

EMG Electromyography f Frequency of breathing

FEV1 Forced expiratory volume in one second

FVC Forced vital capacity

GERD Gastroesophageal reflux disease

GINA15 Global Initiative for Asthma 2015

GOLD Global Initiative for Chronic Obstructive Lung Disease

H2CO 3 Carbonic acid

H2O Water

Hb Hemoglobin

HbO 2 Oxyhemoglobin

HCO 3- Bicarbonate

HHb Deoxyhemoglobin

HV Hyperventilation

ICS Inhaled corticosteroids

IgE Immunoglobulin E

ISAAC The International Study on Asthma and Allergies in Childhood

L Liters

LABA Long-acting beta2-agonist

Log Logarithm

Min Minutes

Ml Milliliter mmHg Millimeter of Mercury

Mmol Millimole

NAEPP National Asthma Education and Prevention Program

NTS Nucleus tractus solitaries

O2 Oxygen

PaCO 2 Arterial pressure of carbon dioxide

PaHCO 3- Arterial pressure of bicarbonate

PaO 2 Arterial partial pressure of oxygen

PCO 2 Partial pressure of carbon dioxide

PEF Peak expiratory flow pH -log [H+]; measure of hydrogen ion activity pK logarithm of dissociation constant, K

PO 2 Partial pressure of oxygen

PRG Pontine respiratory generator

RR Respiratory rate

SABA Short-acting beta2-agonist

SHR Sensory hyperactivity

SIGN British guidelines on management of asthma

U-BIOPRED Unbiased BIOmarkers for the PREDiction of Respiratory Disease Outcome. V’A Alveolar ventilation

V’E Pulmonary ventilation

V´D Dead space ventilation

VRG Ventral respiratory generator

VT Tidal volume

WHO World Health Organization

1 Introduction

Over 2000 years ago, the Greek Hippocrates (460-377 BC) recognized symptoms of abnormal breathing and named these symptoms as a disease asthma. 1 Asthma is nowadays a highly prevalent chronic illness, affecting approximately 300 million individuals worldwide, and the incidences are increasing. Global prevalence of asthma ranges from 1 ̶ 16 %. In Iceland, prevalence of asthma is about 10% in children 2 and 5-7% in adults.3 Almost 14 million disability-adjusted life years (DALYs) are lost annually worldwide, due to asthma. This represents 1.8% of the total global disease burden 4 and is similar to diabetes.5 Both morbidity and mortality from asthma are significant, and it is estimated that 346.000 individuals die worldwide every year because of asthma. 4 The World Health Organisation (WHO) estimates that asthma deaths will increase over the next ten years if urgent action is not taken. 6

Asthma is ineffectively treated despite a better understanding of pathophysiology and new pharmacological strategies. 4 According to WHO, access to cost-effective strategies and asthma medication should be improved to prevent asthma attacks and asthma-related death. 6 Non- pharmacological therapies such as breathing therapies have shown to increase asthma control and quality of life. One of them, the Buteyko method (BM) has garnered interest in the asthmatic population worldwide. 7, 8 BM is a technique that uses breath control to treat asthma and is believed to be connected

9, 10 to low levels of carbon dioxide (CO 2) in the body. There is little scientific evidence that supports the

CO 2 theory of BM. In this study, physiological mechanisms behind the theory such as resting ventilation and chemosensitivity for CO 2 are examined.

1.1 What is asthma? Asthma is an umbrella term for a heterogeneous disease and is characterized by variable airflow limitation, both in time and in intention, due to bronchial contraction, bronchial swelling and mucus accumulation. These can cause various and variable respiratory symptoms, such as wheezing, shortage of breath, chest tightness, and coughing. Chronic inflammation and hyper-responsive airways are common features of asthma.4

Diagnosis The diagnosis of asthma is made according to family and medical history, physical examination, and lung function tests, such as spirometry and peak flow tests (PEF). To diagnose inflammation in the airways, a bronchoprovocation, or challenge, test is done to trigger symptoms and confirm the variable expiratory airflow limitation.

A thorough diagnosis is necessary for good asthma control and management. Asthma is easily confused with asthma-related disorders, like vocal cord dysfunction, airway sensory hyperactivity (SHR), hyperventilation, dysfunctional breathing, non-obstructive dyspnoea, and gastroesophageal reflux disease (GERD). Asthma medications do not offer relief in these asthma-like disorders.11

Risk factors and allergies Fundamental causes of asthma are difficult to establish. Genetic predisposition 12 seems to be a part, but does not explain the increase in asthma prevalence alone. 13 The Unbiased BIOmarkers for the PREDiction of Respiratory Disease Outcome (U-BIOPRED) project, set up in 2009, aimed to identify the heterogeneity of asthma in so-called phenotypes, leading to new treatment targets and better approaches to asthma therapy. 14 Certain risk factors can have an influence on the development and severity of asthma (see Table 1).15 Asthma often involves an inflammatory disorder of the lungs and inflammation can be found in all airways, including the nose, called rhinitis. For example, 80% of asthmatics have rhinitis, and 20-50% of those with rhinitis have asthma.4, 16

Table 1. Potential risk factors for asthma 15

Host factors Age Gender 15 Genetic predisposition 12 Atopy Environmental Factors Early life and social factors Indoor environment Outdoor environment Stress Lifestyle Factors Smoking Diet Obesity and physical activity 17 Gastroesophageal reflux Occupational Factors Work exposures

It is difficult to understand how these risk factors in Table 1 contribute to the development of asthma. However, it is known that some risk factors, also called triggers, have an unyielding influence on asthma. These can be indoor allergens (house mites, pollution, and pet dander), outdoor allergens (pollen and mold), and tobacco smoke. It is estimated that 15% of asthma cases among adults of working age are due to chemical irritants in work places (occupational asthma).4, 18 When one is exposed for a long time to these risk factors, structural changes in the airways, also called airway modelling, are seen and are often associated with chronic allergic inflammation. 19

1.2 Asthma control Asthma control is defined as the “effective management of the clinical characteristics of the disease, including symptoms (such as dyspnea, cough and wheezing), nocturnal awakening, reliever medication

use, activity limitation and lung function”, according to the Global Initiative for Asthma (GINA16) 4. GINA16 defines three levels of asthma control, “controlled/well controlled, partially controlled/ not well- controlled, and uncontrolled/very poorly controlled”. 4

To assess levels of asthma control, the Asthma Control Test TM questionnaire (ACT; Quality Metric Inc., Lincoln, RI, , USA) was concluded to be reliable, valid, and preferred in clinical practice according to a recent review.20 The ACT is a five question, self-administered health survey used to measure asthma control in individuals 12 years of age and older. It has a four-week recall period. The ACT has a cut-off score of 19. Asthma is well-controlled with scores above 19, and not well-controlled with 19 or below. Diary cards are used in studies together with the ACT to recognize fluctuations by recording symptoms, medication usage, or other required measurements.21-23

Control-based asthma management The goal of asthma management is to obtain and maintain control of the disease, with the minimum and adequate level of therapy and minimum side effects. As the variable character of asthma can make it difficult for health care professionals, and asthmatics themselves, to control symptoms, guidelines are focused on levels of asthma control, rather than disease severity. 24 Proper diagnosis by trained health care professionals, a good patient-doctor relationship, patient education, self-management, avoidance of exposure to triggers and adherence to treatment are recommended to achieve control and reduce asthma-related deaths, according to WHO. 6

Asthma management should prevent exacerbations, decreased lung function, and adverse side effects of medications by using the lowest possible medication dosage. Supervised medication management is required based on guidelines. These guidelines mostly provide a stepwise medication strategy according to levels of control. As for the bronchoconstriction component, asthma is managed by a combination of short-acting B2-agonist (SABA) and/or long-acting B2-agonist (LABA). For the inflammatory component, asthma is controlled by inhaled and/or oral corticosteroids as a treatment or as a preventative measure.4

Demoly et al. 25 showed that 6.1% of the adult population in five countries in Europe (about 15 million people) are diagnosed with asthma. Of these, 57% of asthmatics who were treated for their asthma were not well-controlled. As asthma control decreased, direct costs (hospital admission and increased use of medication) and indirect costs (time lost from work and premature death) for asthmatics increased. 5, 25 Papaioannou et al. 24 concluded that, world-wide, asthma is controlled only in a small percentage of patients. Reasons for this are a lack of understanding or misunderstanding of disease mechanisms, inadequate adherence to treatment, and a lack of good patient-doctor relationships. Also, continuous exposure to irritants and the presence of comorbidities are suggested to be causes of not well-controlled asthma. To access effective management and achieve better control, specialized healthcare and, most importantly, a better understanding of disease mechanisms are required. Severe asthma is an important problem, which needs to be focused on. 24 In a meta-analysis of placebo-controlled trials of asthma medication dosages, Salpeter et al.26 concluded that regular B 2-agonist usage over one week resulted in tolerance to its effects and poorer disease control. In this analysis, some of the investigated research was funded or sponsored by

pharmaceutical companies and some was not. Of this, 73% of the funded research concluded that B 2- agonist usage was of benefit for asthmatics. Only 10% of the unfunded research confirmed B 2-agonist usage to be of benefit for asthmatics. In a recent Cochrane overview of reviews 27 it is concluded, that regular B2-agonist medication usage increased the risk of fatal and non-fatal serious adverse events for adults or adolescents with asthma.

Psychological factors. Emotional disorders, such as anxiety and depression can have an impact on asthma control.28 These disorders are more frequent among asthmatics and can make asthma symptoms more prominent, although asthma is not a psychosomatic disorder. Vice versa, asthma symptoms themselves can increase anxiety and panic, and worsen psychosomatic disorders. This process might result in, or be the result of, disproportionate breathing behaviours, or dysfunctional breathing.29, 30 Pbert et al. 31 , suggested that relaxation techniques (mindfulness-based stress reduction) improved the asthma-related quality of life, and this was seen without decline of lung function. Unfortunately, there is no validated method to evaluate psychological effects on asthma control. 29, 32 When emotional stress makes asthma worse, GINA16 advises the use of relaxation techniques and breathing exercises to achieve better asthma control. 4

Posture and physical condition Posture and physical condition are important for the functionality of ventilation in rest. They influence the mechanical interaction of lung, chest wall, and intra-abdominal pressure, and the vulnerable process of synchronized activation of the diaphragm and inspiratory muscles. 33 Breathing becomes dysfunctional when this biomechanical function is inappropriate and inefficient due to bad posture and bad physical condition, and this influences asthma control. 34

The diaphragm is the main inspiratory muscle. The synchronous transmutation of the diaphragm from parachute shape to disk form and back is restricted by many factors because of a lack of stability in this movement. The tension provoked by the push-pull mechanics of organs above and below the diaphragm is the only stabilization for the diaphragm. This explains the vulnerability of the efficiency of the diaphragm and mostly depends on posture and the elastic firmness of tissues such as the diaphragm itself, the respiratory and pelvic floor muscles, the abdomen viscera, and of the rib cage. 35, 36

In asthma, the slightest tension and/or mucus accumulation in the bronchi increases deep inspirations. The auxiliary muscles, as scalenii, the sternocleidomastoids, and the trapezuis, become more activated and try to decrease the feeling of dyspnea, leading to higher costal and dysfunctional breathing patterns. Van Dixhoorn et al. 36 explained that dysfunctional breathing patterns create a continuous range of adaptations and adjustments of respiratory muscles and muscular activity in the whole body, resulting in bad posture. By correcting bad posture habits and training straight posture, the functionalilty of the biomechanics of breathing improves. Hodges et al. 33, 37 demonstrated that the efficiency of the diaphragm is reduced when the central ventilatory drive is increased. Deep inspirations resulted in increased tension of the diaphragm, changed posture, and an increased central ventilatory drive is related to dysfunctional breathing.

1.3 Ventilation at rest Ventilation has multidimensional functions which are interactive. It has both psychological and physiological components, either of which can become disturbed and result in dysfunctional breathing.38 Thomas et al. 39 concluded that 30% of asthmatics are affected by dysfunctional breathing in terms of breathing in excess of metabolism or hyperventilation. However, the pathophysiology of hyperventilation is not completely understood yet 38, 40-42 and difficult to relate to asthma. One of the main symptoms of asthma is breathlessness or dyspnea. When in dyspnea, asthmatics feel the need to breathe more 43 and studies have shown hyperventilation to be present in asthma attacks 44 and in asthmatics. 39, 45-47 In order to explore what is known about ventilation and asthma, the physiology of resting ventilation is examined and related to asthma. Chemosensitivity to CO 2 in breathing control and the relation between asthma and CO 2 are emphasized to assess whether or not asthmatics hyperventilate at rest.

The Respiratory system Function of the respiratory system

The respiratory system has two primary functions. The first function is respiration, which can be divided into external and cellular respiration (see Figure 1). External respiration is the gas exchange of oxygen

(O 2) and CO 2. It occurs together with the circulatory system and between the atmosphere and the body.

External respiration can be separated in four processes, a) the exchange of CO 2 and O 2 between the atmosphere and the airways, or ventilation, b) the diffusion of O 2 and CO 2 between the airways and the pulmonary capillaries, c) the transport of O 2 and CO 2 in the blood, and d) the diffusion of these gases between the blood and the cells.

Figure 1. The respiratory system. One main function of the respiratory system is the gas exchange in 4 phases: ventilation, transport, diffusion to cells, and oxidation in cells. The other main function is the maintenance of the acid-base balance (pH).48

Cellular respiration is when oxygen reacts in the cells with nutrients like fatty acids, carbohydrates (glucose) and amino acids. The reaction provides energy and creates carbon dioxide, water, and waste products. The purpose of cellular respiration is to obtain energy by burning oxygen in the cells. The other primary function of the respiratory system is to maintain the acid-base balance (pH) in the blood stable, together with buffer- and renal system. 49

Structure of the respiratory system

The respiratory system is not simply the airways, the lungs and the muscles of respiration. It also includes the chest wall, important because of the mechanical interaction with the lungs, and the central nervous system that is concerned with the control of ventilation.

The airways may be divided into two parts: the upper and lower respiratory tracts. Air enters through the nose and/or mouth. The upper airway: mouth, nasal cavity, pharynx, and larynx, are essential for conditioning the air before it reaches the lungs and alveoli. Breathing through the mouth is not nearly as effective as breathing through the nose; the nasal cavity filters out bacteria, viruses and other unwanted material. It warms outside air to body temperature (37º) and adds water or vapour until the air reaches 100% humidity, so that the inner surface (epithelium) of the lungs do not dry out. 49, 50 It matters whether asthmatics breathe through the nose or mouth. Oral breathing can cause a decrease in lung function in mild asthmatics at rest. It can initiate asthma symptoms in some, and it may play a role in the

pathogenesis of acute asthma exacerbations. 51, 52 Nasal breathing is important for asthmatics. It is shown that impaired nasal function affects the lower airways in asthmatics. 16

The lower respiratory tract consists of the trachea and two primary bronchi, each dividing from 10 to 23 times before terminating in a cluster of alveoli in the lungs (see Figure 2). The first 16 bronchioles, or the conductive zone, contain no alveoli and their walls are too thick for gas exchange with venous blood. The area from the beginning of the mouth and nose through the conductive zone is called the anatomic dead space. The structure of the airways varies, dependent on their location in the tracheobronchial tree. The trachea is a fibromuscular tube, supported by C-shaped cartilage. The cartilage support diminishes progressively in distal airways. Cartilage support disappears in airways with a diameter of 1 mm, called bronchioles. 49

Figure 2. Airway branching in the lower respiratory tract. The conducting system is part of the anatomic dead space where there is no gas exchange. The exchange surface is for diffusion of gases. 48

The diameter of these bronchioles is regulated primarily by the autonomic nervous system and locally, among other factors, by levels of CO 2 in air passing through them. If levels of CO 2 fall, as in breathing in excess of metabolism or hyperventilation, the bronchioles constrict. If levels rise, they dilate. 49 Most of the respiratory tract is coated by mucus-covered, ciliated epithelium. When asthma symptoms are present, the epithelium often produces more mucus and is thickened, diminishing the radius of the bronchioles and narrowing the respiratory tract (see Figure 3). 49

Figure 3. Normal bronchial tube at left side and narrowing of the bronchial tube in asthma at right side of picture. 53

Diffusion of O 2 and CO 2 takes place through the alveoli and their associated pulmonary capillaries, or the alveolar-capillary interface. The ventilation/perfusion ratio (V’/Q’ ratio) in respiratory physiology is a ratio used to assess the efficiency and adequacy of the matching of two variables: V’, ventilation or the air that reaches the alveoli and Q’, perfusion or the blood that reaches the capillaries surrounding the alveoli . The surface area and thickness of the alveolar-capillary membrane is important for diffusion. 49

The transport of oxygen and carbon dioxide.

Less than 2% of O2 is transported dissolved in the blood. About 98% is chemically bound to the protein hemoglobin (Hb), situated in the red blood cells, or erythrocytes. The amount of Hb present in blood is important for the capacity and the content of O 2 in blood. The percent saturation (% Hb saturation) expresses the proportion of Hb bound to oxygen. The affinity of Hb for O2 is expressed in the oxyhemoglobin (HbO 2) dissociation curve.

Several mechanisms have an effect on the percentage of Hb saturation and the availability of O 2 for metabolism. It starts to be critical when the partial pressure of oxygen (PO2) falls below 60 mm Hg. At this state, Hb is 90% saturated (see Figure 4), with a normal partial pressure of CO 2 (PCO 2) of 40 mm Hg.49

Figure 4. The hemoglobine saturation curve for partial pressures of oxygen. The effect of different 48 partial pressures of CO 2 (PCO 2) on hemoglobine saturation.

However, in situations of hyperventilation (PCO 2 is 20 mm Hg), the dissociation curve shifts to the left

(see Figure 4). Hyperventilation increases the affinity of Hb for O2 and off-loading of O2 on the tissues will be reduced. 49

The tissues are vascularized by a fine capillary network. There, the exchange of O 2 and nutrients diffuse out of the blood into the cells. About 5-10% of the CO 2 is transported in the blood dissolved in the plasma, 20% bound to Hb and 70% as bicarbonate (HCŌ 3 ̄), an important buffer for the pH in blood.

Venous blood returning from body tissues containing a high concentration of CO 2 and a low concentration of O 2 is pumped from the right ventricle of the heart into the lungs, where CO 2 is exhaled

49, 54 and O2 is inhaled.

Pulmonary ventilation In physiology, the exchange of gas between the lungs and the atmosphere is called the pulmonary ventilation (V’ E), measured as litres per minute (L/min). Pulmonary ventilation is a combination of gas that exchanges with pulmonary blood, or alveolar ventilation, plus gas that does not exchange with pulmonary blood, or dead space ventilation. Ventilation is dependent on the tidal volume, or the amount of air inhaled within each breath, (V T, L) and the frequency of breathing (f, breaths /minute), described

49 with the formula V´ E = V T x f. Pulmonary ventilation at rest ranges much or from 4-7 L/min. It is important to relate resting ventilation to metabolism, as big men have to breathe more air than small women. 49 Some studies 55-57 have examined resting ventilation in asthmatics, but they have not related these measures to metabolism. Such results are difficult to evaluate.

Alveolar ventilation

Alveolar ventilation (V’ A) is the airflow that enters the alveoli, measured as litres per minute (L/min). It represents inspired air with 20-21% of O2 and 0.03% of CO 2, and in a similar volume of expired air, with

16-17% of O2 and 3-4 % of CO 2 leaving the functioning alveoli at rest. When V’ A is high

(hyperventilation), PO 2 increases and PCO 2 decreases in the alveoli. When V´ A is low (hypoventilation),

the PO 2 decreases and PCO 2 increases (see Figure 5). Functionally, V´ A should be examined relative to what is required by metabolic demands. In rest, hyperventilation is when V’ A is more than metabolic demands, as for example in stressful and emotional situations.49

Figure 5. Hypo- and hyperventilation. In hyperventilation, alveolar partial pressure of oxygen is higher and of carbon dioxide is lower than in normal ventilation. And vice versa in hypoventilation. 48

Dead space ventilation Gas that does not exchange with pulmonary blood, or dead space ventilation is not included in alveolar ventilation. Alveolar ventilation is pulmonary ventilation without dead space ventilation. The dead space is composed of two parts: anatomic and alveolar dead space. Anatomic dead space is the area from the beginning of the mouth or nose through the conductive zone (see Figure 2). After each inspiration, an amount of air stays in the conductive zone i.e. dead space volume (V D) and this fresh air has the same composition as the outside air. After each expiration, an amount of air does not leave the lungs and that air has the same composition as the alveolar air (see Figure 6). Studies have tried to estimate this space with non-invasive methods. 54, 58 In asthma, this space can alter as the tension in the bronchi changes. Additionally, traction or compression (as sitting straight or bending) increases and decreases anatomic dead space respectively. The smaller the tidal volume, the greater the percentage lost to anatomic dead space ventilation for each breath. 59

The alveolar dead space refers to ventilated but non-perfused alveoli in the lungs. Alveolar dead space is most often more in asthmatics although it varies considerably, because of the variable

58, 60 ventilation-perfusion (V’A/Q’) mismatch in the alveolar-capillary unit caused by bronchoconstriction.

The V’ A/Q´mismatch is an important factor when interpreting values of resting partial pressure of end- tidal CO 2 (PET CO 2) in asthmatics. Measures of P ET CO 2 are used to estimate measures of partial

41, 54, 60 pressures of arterial CO 2 (PaCO 2) for normal subjects. Measures of PET CO 2 are taken at the end of quiet exhalations, providing the best conditions to resemble PaCO 2. For asthmatic subjects, the

relation between PET CO 2 and PaCO 2 has differed because of the ventilation and perfusion mismatch

(V´ A/Q’) in the alveoli. Depending on the severity of this mismatch, differences can be seen in lower values of P ET CO 2 than real values of PaCO 2. To make precise measures in asthmatics, a blood gas

58 sample is needed to get exact measures of PaCO 2.

Physiologic dead space is the sum of alveolar and anatomic dead space. Inspired air from these areas will leave the body as it entered, contributing no CO 2 to exhaled air. Thus, the greater the

49 physiologic dead space, the less the CO 2 in exhaled air. Dead space ventilation has no physiologic advantage and, if increased, more energy must be wasted to move additional gas so that alveolar ventilation can be maintained. This conforms to breathing ineffectively and dysfunctional.

Figure 6. The anatomic dead space. After each inspiration, an amount of air stays in the conductive zone. During expiration, the air in these conductive zones has the same composition as the inspired air. After each expiration, an amount of air does not leave the lungs. 48

The bicarbonate buffer system The bicarbonate buffer system helps, together with the respiratory and renal system, to maintain a constant internal environment in the cells and the body (homeostasis) by keeping a balance between acids and bases.

A buffer system is a mixture of an acid and a base that resists changes in its pH. The bicarbonate

+ buffer system is closely linked to pH through the bicarbonate buffer formula, CO 2 + H 2O ↔ H 2CO 3 ↔ H

+ HCŌ 3 ̄. Weak carbonic acid (H 2CO 3) and an HCŌ 3 ̄ base are a buffer pair. The buffer value is expressed by the Henderson-Hasselbach equation: pH = pK + log [HCŌ 3 ̄] / [CO 2 + H 2CO 3] where K is the dissociation constant and [HCŌ 3 ̄] is the plasma bicarbonate concentration. Because it is a weak acid,

the H 2CO 3 concentration is negligible. The ability of this buffer system depends on V’ E, as V’ E controls

49 the levels of CO 2 in the body. Higher pH values are seen in acute hyperventilation, but with chronic hyperventilation pH values are stable and approach normal values.61, 62

Spirometry Spirometry testing is done to assess lung function (see figure 7). Spirometry values are compared to predicted values according to the gender, age, height, mass, and ethnicity of the participant. The most common spirometry values are the forced vital capacity (FVC) and the forced expiratory volume in one second (FEV 1). FVC measures the amount of air from the start of a maximal inspiration until the end of a maximal forced expiration. The volume of air expired in the first second is a good index of expiration airways resistance, especially when expressed as ratio with FVC .

Figure 7. Spirometry, a volume-time graph. The proportion of the amount of air, starting after a 48 maximal inspiration, of forced expiration in one second to forced vital capacity (FEV 1/FVC). FET= forced expiratory time .

4 In asthma, values lower than 0.7 of the ratio FEV 1/FVC indicate obstruction of the expiratory airflow.

Measures of FEV 1 compared to predicted values lower than 80%, indicate the severity of the obstruction.63 Meuret et al. 61 showed that deep and fast breathing, as in spirometry, can lead to airway obstruction and increase asthma symptoms in asthmatics, while deep inhalations provoke bronchodilation in healthy airways. 64

Fenger et al. 65 demonstrated, that changes in weight had an impact on lung function testing.

Increasing adiposity resulted in a decline of FEV 1 and FVC, but not FEV 1/FVC. The opposite was also true, decreasing adiposity increased FEV 1 and FVC but not FEV 1/FVC.

Ventilation musculature The respiratory muscles are skeletal muscles (see Figure 8). The group of inspiratory muscles includes the diaphragm, the external intercostal, parasternal, sternocleidomastoid, and scalene muscles. The group of expiratory muscles includes the internal intercostal muscles, the rectus abdominis, the external and internal oblique muscles, and the transverse abdominal muscles. During ventilation at rest, only the inspiratory muscles are active. During increased breathing efforts, the expiratory muscles become active as well. At this time, respiration is coordinated by a combination of diaphragm and transverse abdominal

muscle activitiy. 33 The respiratory muscles themselves use 5% of total oxygen uptake, can get tired, and can be trained. 66, 67

The main work of breathing by respiratory muscles, is to overcome the elastic recoil of the lungs and chest wall, but also the resistance to air flow. Airway resistance is about 35% to 50% in the upper airways. Airway resistance is higher while breathing through the nose than through the mouth. In normal conditions, the radius of the bronchi decides the resistance of the airways. In asthma, the bronchi with the smallest radius causes the highest resistance (see Figure 3). 49

Figure 8. Muscles of breathing. Muscles of the thorax, neck, and abdomen create the pressure difference to move air during ventilation. 48

Breathing control Control of breathing is of vital importance to keep the internal environment of our cells constant, one of the most important physiologic functions of the body. Failure is not an option. Normally, the human body cannot be without ventilation for more than three minutes. In comparison, we can be without food for about three weeks and without water for about three days. 49

Ventilation is spontaneously triggered in the central nervous system. It is controlled by a fine-tuned system, aiming at an efficient utilization of blood gases such as CO 2 and O 2 to keep the pH constant. The goal of this system is an effective, functional breathing mechanism with a minimum of work and a minimum of metabolic cost of each breath.

Figure 9. A control system has three interconnecting components. Central respiratory centers in medulla oblongata change ventilation by controlling respiratory muscles, according to inputs from chemosensors, the lungs, and other receptors. 49

The respiratory control system has three, interconnecting components (see Figure 9). The first component (central controller) are the respiration centers, which are distributed in the reticular formation of the medulla oblongata. A complicated synaptic interaction between several neurons in these medullary respiratory control centers effectively change and adapt ventilation. Pacemaker-like neurons in the pre-Bötzinger complex, called the central pattern generator (CPG), are situated in the ventral respiratory groups of the medulla. They generate the timing and the amplitude of respiratory muscles with a highly regulated lability, modulated by pontine and other inputs.68, 69 The CPG is automatically modified while talking, singing, or blowing. Dysfunctions of the CPG can result in diseases. 48, 68

Secondly, sensory inputs (sensors) from higher brain centers and from central and peripheral chemosensors consistently influence these respiratory control centers in the brain. Other contributors are sensory inputs from the lungs, the cardiovascular system, the skeletal muscles, and tendons of respiratory muscles. The third component (effectors) is the synchronized distribution of motor output to the respiratory musculature controlling ventilation. The respiratory control system needs further

70 exploration in order to be able to evaluate how breath control and chemosensitivity for CO 2 are related. The underlying mechanisms of neural control of ventilation are still not completely understood. 49, 68

The spontaneous central pattern generation of respiration can be overwhelmed by centers from the cortex and human will. They may have a direct influence on the muscles of breathing (diaphragm and auxiliary muscles), as with breath holding. Other cortex centers, where experiences of stress and emotions as depression, anxiety, and happiness arise, can initiate widespread ventilatory responses throughout the body. Emotions and respiration are closely linked in a complex feedback system through the autonomic nerve system (ANS). Severe and persistent emotional states can cause chronic hyperventilation, resulting in a sympathetic dominance of the ANS. During meditation and breathing practices, there is a shift from sympathetic to parasympathetic dominance in the ANS. This results in decreased respiratory activity and reduced negative emotions. 71-74

Chemosensors According to physiology, a respiratory chemosensor is a receptor that detects alterations of its direct chemical environment and adjusts respiratory activity through the central nervous system. 49 Control of

75 breathing by chemosensors can be seen as a feedback control system. V´ E controls levels of PaCO 2 and PaO 2, and respiratory chemosensor reflexes control V´ E, apart from influences of higher brain centers. The respiratory chemosensor reflexes are responsible for controlling PaCO 2 and keeping hydrogen ion concentrations (H +) within certain values. There are two types of chemosensors, the central chemosensors, located distributed in the medulla, and the peripheral chemosensors, located in the carotid and aortic bodies.

Figure 10. Central (left-side of picture) and peripheral chemosensors (right-side). CO 2 flows into the cerebrospinal fluid through the blood barrier, a highly selective permeable membrane, separating arterial blood from cerebrospinal fluid, keeping the brain safe. This increases ventilation through the reduced pH, sensed by the central chemoreceptors, activating the respiratory control center. Increased PaCO 2 also stimulates peripheral chemoreceptors, activating respiratory control centers. Through a negative feedback system of higher amount of O 2, and lower amount of CO 2, the respiratory control center is inactivated. 48

Central respiratory chemosensors lie in brain extracellular fluid (ECF) and are surrounded by cerebrospinal fluid (CSF). They are effected by local metabolism (see Figure 10). The blood-brain barrier separates respiratory chemosensors from arterial blood and is highly permeable for PaCO 2. It is difficult

+ for HCO 3- and H to cross this barrier. Hence, the respiratory chemosensors are not sensitive to CO 2,

+ but to H concentrations. When V’ E changes, PaCO2 and pH change in the blood, resulting in changes

in levels of CO 2 in the CSF. In CSF pH changes also, according to the bicarbonate buffer system formula

+ ↕CO 2 ̄ H2O ↔ H 2CO 3 ↔ ↕H + HCŌ 3 ̄. In response to changes in pH, the central chemosensors stimulate/inhibit the respiratory centers, controlling respiratory activity through this feedback system.49 It is very important to maintain pH, or H +, levels within certain limits in the CSF. Maintaining pH is done

- by keeping the ratio of CO 2 to HCO 3 constant, as expressed by the Henderson-Hasselbach equation

+ H = CO 2/ HCŌ 3 ̄ or pH = pK + log (HCŌ 3 ̄ /CO 2). Regulation of pH in the CSF is made more rapidly than blood pH (because of a lack of hemoglobin in the CSF).

76 Under resting conditions ventilation is mostly regulated by CSF pH, directly reflexing PaCO 2 , and pH disturbances in CSF are resisted by modulating V’ E. In other words, ventilation is a mechanism for regulating the acidity of the blood and of the CSF through the controlled release of CO 2. Furthermore, the ventilatory drive is dependent on the threshold values of CO 2, which stimulates or inhibits breathing at the central level. With breath holding, levels of PaCO 2 increase until the threshold value of CO 2 has been reached, expressing the chemosensitivity of the ventilatory drive. Because V´ E controls PaCO 2, persistent changes in V´ E can alter the ventilatory recruitment threshold of PaCO 2. Where habitually or chronic hyperventilation develops, the central respiratory control centers become more sensitive for CO 2 as a state of chemo hypersensitivity. They trigger breathing at lower levels of PaCO 2, maintaining a

75 62 hypocapnic state (low PaCO 2). Laffey et al. related asthma to hyperventilation and to causes of hypocapnia. This state can be intermittent or persistent as asthma symptoms fluctuate widely. Kassabian et al. 77 showed a raised respiratory control sensitivity in asthma and Hide et al. 78 demonstrated that the central respiratory control centers have a key role in determining the severity of asthma.

The peripheral chemoreceptors, located in the carotid and aortic bodies, lie at the fork of the common carotid arteries that supply the brain with blood. They are sensitive to low PaO 2, low pH, and high PaCO 2.

They are maximally stimulated when PaO 2 decreases below 50-60 mmHg, as can be the case with severe asthma attacks. The reflex of the peripheral chemoreceptors increase ventilation and constrict the bronchi but dilate upper airways. 76 The peripheral chemoreceptors sensitize the central pattern generator through both ventilation and sympathetic nerve activity, even for a prolonged time after cessation of input. The ventilator control system is highly flexible in response to this chemoreceptor stimuli, even during exercise and sleep.68

A large number of other sensors located in the lungs, the muscles, tendons, and skin have an influence on the respiratory control centers. Pulmonary stretch receptors decrease respiration through the central nervous system. Receptors in the nose, mouth, and upper airways (irritant receptors) keep the airways open when pressure falls in the upper airways (with cough and sneezing reflexes). Temperature increases respiratory rate, and sudden pain decreases it. Prolonged pain, on the other hand, increases respiratory rates. 49

Physiological efficient and functional ventilation Efficient ventilation should be assessed in relation to metabolism. There has to be a balance between metabolism and ventilation or between O2 demand and supply at the tissue level. Ventilation is normal when a balance between metabolism and ventilation is achieved without compensation mechanisms

(such as bronchoconstriction) i.e. when there is a balance between CO 2 production and CO 2 exhalation. 9, 49

Courtney et al. 79 examined the functionality of ventilation at rest. Comprehensive evaluation of the various aspects of ventilation should include physiological measures, breathing symptom questionnaires and tests of breathing function such as BHT. The function of the biomechanics of ventilation at rest can be influenced by posture 37 , physical conditions80 , and breathing techniques 81 . The efficiency of the biomechanics of ventilation can have an influence on asthma control. Straight posture, ensuring optimal diaphragmatic breathing and good physical condition are contributory to asthma control.34 Measures such as V´ E and PaCO 2, are essential to evaluate the functionality of ventilation at rest, because of their

49, key role in central respiratory control and the balance between CO 2 production and CO 2 exhalation. 62

Metabolism

To interpret the efficiency of ventilation at rest, it should be corrected to metabolism. Metabolism is al biochemical processes that occur in the body in order to provide the cells with their needs and to maintain homeostasis. Metabolic rate is mostly dependent on gender, age, surface of the skin, and muscle mass. Gas exchange, O2 consumption (V’O 2), and CO 2 output (V’CO 2), are indicators of metabolism. An important measure of ventilation is the ratio between the volume of gas breathed out

(V’ E) in litres per minute to V´CO 2 (V’ E /V’CO 2) in litres per minute. This ratio is called the ventilatory equivalent of CO 2 and is meant to reflect the efficiency of ventilation. Normal values of the ventilatory

82 equivalent at rest have not yet been established. Habedank et al. found lower rates of V’ E/V’CO 2 at rest for men than for women (50.5 ± 8.8 versus 57.6 ± 12.6, p < 0.05). Ventilatory efficiency at rest was depended primarily on age and gender in that study. If ventilation is in excess to our metabolic rate, we hyperventilate. When hyperventilating, the ventilatory equivalent will increase, PaCO 2 will decrease, and

PaO 2 will increase. It is presumed that the ratio of V’A /V’CO 2, compared to V’ E ̸ V’CO 2 gives an indication of ventilation in physiologic dead space at rest . The greater the difference between V’ A /V’CO 2 and V’ E ̸

V’CO 2, the more energy is wasted in dead space ventilation. This could indicate dysfunctional breathing.

Hence, to obtain precise measures of V´ A, blood gas samples are needed.

Meditation and SABA use have an influence on resting metabolism. Wallace et al.83 and Wolkove et al.74 showed that reducing ventilation regularly, as in meditation, can result in lower metabolic rates. Agha et al. 84 demonstrated a direct positive correlation between metabolic rate at rest, asthma severity, and impairment of lung function. They showed that B2-agonist medication increased the metabolic rate

85, 86 of asthmatics, and more studies have confirmed metabolic side effects of B 2-agonists in asthma.

1.4 Asthma and resting ventilation How do asthmatics breathe in rest when they are symptomatic? Do asthma symptoms cause hyperventilation, or does hyperventilation cause asthma symptoms? Normally, when asthma symptoms occur, ventilation increases because of the feeling of dyspnea caused by bronchoconstriction. Irritant receptors in the airways, stimulated by increased mucus, also causes increased ventilation, that result

in hypocapnia and a disturbance in pH.49 According to this, asthma symptoms cause hyperventilation.

Only very severe asthma attacks cause high values of CO 2 (hypercapnia) and low values of O2 (hypoxia). Due to severe bronchospasm and dyspnea, it is difficult for people with severe asthma symptoms to do the work of breathing. Severe bronchospasm and dyspnea result in a cycle of progressive hypoxia (stimulating the peripheral chemoreceptors 68 ), hypercapnia, fatigue, and respiratory failure. 62 Hyperinflation can be a consequence of chronic severe asthma. 87

Can hyperventilation cause asthma symptoms? Laffey et al. 62 explained how hyperventilation is related to low baseline levels of PaCO 2 (hypocapnia). Hypocapnia is expressed by the equation: PaCO 2

= CO 2 production/ CO 2 exhalation + inspired CO 2. As the production of CO 2 is not the cause of low

Pa CO 2 levels, and inspired CO 2 is negligibly low, the principle physiologic cause of hypocapnia is

40, 88 related to hyperventilation. Studies have shown that levels of PET CO 2 in rest can be normal in people with symptomatic hyperventilation. It seems more likely, that during symptomatic hyperventilation, levels

89, 90 of P ET CO 2 fluctuate rather than becoming chronically low. Experimental evidence supports the potential role of hypocapnia in asthma. Van den Elshout et al. 91 found a relation between hypocapnia and respiratory resistance in asthmatics, caused by bronchoconstriction. Decreased P ET CO 2, 7.5 mmHg, resulted in 13% increased respiratory resistance in asthmatics, but not in non-asthmatic subjects, demonstrating that hypocapnia is a possible cause of asthma symptoms. When PET CO 2 was increased, respiratory resistance reduced in both healthy and asthmatic subjects. Hypocapnia also shifts the oxyhemoglobin curve to the left (see Figure 4), restricting offloading of oxygen to the cells, resulting in less oxygen supply to the cells (Bohr effect), or tissue hypoxia. Hypocapnia may create a more anaerobic metabolism, causing the accumulation of organic acids. In other words, the more we breathe, the less oxygen we have for metabolism. 41, 62 This evidence suggests that there is a link between hyperventilation and decreased oxygen supply at the cellular level. Finally, when hyperventilation becomes chronic, the central respiratory control centers seem to become more sensitive, triggering

62, 75 breathing at lower levels of CO 2. As seen before, raised central respiratory control sensitivity has

62, 77, 78 been related to asthma. Other studies have examined the role of CO 2 in asthma and shown asthma to be related to hypocapnia. Hence, evidence of hyperventilation in asthma is not clear and further studies are needed. 7, 47, 60, 62

Asthma and breathing therapy Non-pharmaceutical therapies for asthma used with or instead of conventional therapies, have garnered growing interest in a group of the asthmatic population.92 Concerns and dislikes about medications, particularly of inhaled and oral corticosteroids, have caused poor medication compliance.46, 93 Plus, severe asthma has shown to be difficult to control. 93, 94 People with uncontrolled asthma are more likely to use non-pharmaceutical therapies. 92

Studies 92-95 have shown that breathing therapies are the most used complementary, non- pharmaceutical therapies for asthma. GINA16 4 recommends breathing therapies as a complement to conventional asthma management. Slader et al. 81 suggested that features of breathing therapies, such as relaxation, voluntary reduction of rescue medication, and self-efficacy, were the primary reasons for

improvement in asthma control and not the breathing exercises themselves. GINA16 4 discusses the need for high quality studies to test the efficacy of breathing therapies.

Several reviews 7, 8, 96 showed that breathing therapies may decrease the use of SABA, and that they may improve symptoms, quality of life, and psychological outcomes, but not physiological outcomes. All methods provide instructions on nose and diaphragmatic breathing, reduced ventilation, and daily training. Offering breathing therapies by physicians is effective for asthma management. 8 However, it is still uncertain what the best and most efficient training method is. Inconsistent outcome measurements at baseline, and after a retraining intervention, make it difficult to point out a single, best therapy, according to the review of Bruton et al. 7 The most frequently mentioned breathing exercise program in studies is the Buteyko Method. 8, 97-102

1.5 The Buteyko method The Buteyko method (BM) is a structured, health-promoting method for children and adults with asthma 9, 10 . BM shows no evidence of adverse effects. 21 It is acknowledged by the GINA16 4, the British guidelines on management of asthma (SIGN 141) 103 , and by guidelines for the physiotherapy management (joint BTS/ACPRC guideline).104 The method is complemental to conventional therapy strategies and does not conflict with medication use. 4, 103, 104 Systemic reviews of breathing methods also suggested BM to be efficient for asthma management. 7, 8, 104

The BM is focused on reducing ventilation gradually, tidal volume at first and frequency when advanced in the trainings. The BM is based on the theory that asthma can be reversed. It claims hidden hyperventilation leads to excessive losses of CO 2, and this is a fundamental cause of asthma. To adjust the CO 2 balance, the asthmatic body develops defensive reactions such as asthma. The aim of BM is to normalize levels of CO 2 systematically by gradually decreasing ventilation, and matching it with metabolic needs. Progress or lack of progress is evidenced by breath holding time (BHT), a non-effort demanding measurement that is standardized in this method. BHT is an indicator of the chemosensitivity

70 of CO 2 , but also gives valuable feedback for asthmatics about their health level, risk estimations of symptom recurrence, and exacerbations. 9, 10 The BM differs from other breathing techniques, because of the BHT feedback system.

The overall complex treatment procedure consists of a combination of breathing instructions, with both mental and physical components. These include awareness, breathing- and relaxation therapies, together with common, and also individual advice about nutrition, physical activity and general health. By these direct and indirect techniques, the BM gradually and unconsciously resets breathing patterns. The essence of the technique of the method is decreasing the depth of breathing. This is done in daily training sessions by relaxing conscious and unconscious all the muscles that potentiate the breathing action until a very slight lack of air is felt. The sensation of slight breathlessness is maintained by keeping the breathing muscles relaxed, particularly around the shoulders and chest, and by a slight tension of the transverse abdominal muscle. Sitting straight and breathing through the nose while training is essential to obtain success.

In a formal Buteyko session, training starts and ends with measuring BHT. A session has been successful when BHT is longer at the end of the session. Formal training session duration is 15 to 30

minutes. Training should be done at least twice a day, upon waking and before sleep. Some common advice to prevent deep breathing in daily life is included. For example, to control and prevent deep breathing while sleeping, it is advised to wrap a non-elastic tissue tight around the upper chest . Asthmatics themselves have found it useful while sleeping to close the mouth loosely and carefully with a light adhesive tape, to avoid breathing through the mouth. Sometimes it is even necessary to encourage awakening at night to prevent nocturnal asthma symptoms. Coughing and talking techniques are taught when needed, aimed at reduced breathing. Coughing should be performed calmly and efficiently and followed by a holding the breath for a very short period without discomfort afterwards. Talking should be done calmly, with inspirations through the nose. Physical activity is advised according to BHT measurements. When BHT is below 10 seconds, only very light physical activity is advised as walking slowly. When BHT is between 10 to 20 seconds, light physical activity is encouraged as walking and cycling with nose breathing. When BHT has reached over 20 seconds light moderate training is advised daily, with intervals if necessary in the beginning to keep up nose breathing. When physical activity leads to dyspnea, exercise intensity should be lowered. In general, until BHT has reached 60 seconds, physical training should always be guided with BHT measuring and should lead to higher BHT after training. This is important advice for asthmatics in order to be able to increase their BHT over time.

Research on BM Several studies on BM have been published.21, 34, 55, 105-111 They mainly investigated the clinical effectiveness of treatment for asthma. Six of them were randomised, controlled trials (Table 2).

Table 2. Randomized control trials involving BM

First author (date) Study participants Study design Significant Results of BM 1) Bowler (1998) 55 39 adults in 2 groups 1. BM vs. ↓Medication use 2. Relaxation ↓MV + breathing exercises 2) Opat (2000) 109 36 adults in 2 groups 1. BM video vs. ↓Medication use 2. Placebo video ↑QoL 3) Cooper (2003) 106 90 adults in 3 groups 1. BM vs. ↓Symptoms 2. Yoga device vs. ↓Medication use 3. Placebo device 4) McHugh (2003) 108 38 adults in 2 groups 1. BM vs. ↓Medication, also ICS use 2. Education +relaxation 105 5) Abramson(2004) 95 adults in 4 groups 1. BM + placebo video vs. ↑PET CO 2 (4 vs. 3) 2. Asthma education ↓Medication use + Buteyko video vs. 3. Asthma education

+ placebo video vs. 4. BM + Buteyko video 6) Cowie(2008) 21 56 adults in 2 groups 1 .BM vs ↓Symptoms 2. Physiotherapy ↓Medication, also ICS use 7) Prem (2012) 110 120 adults in 3 groups 1. Buteyko vs. ↓ Qol 2. Pranayama yoga ↓ Symptoms 3. Control group ↓ Medication use

MV=minute ventilation; QoL=quality of life; ICS=inhaled corticosteroid; PET CO 2= partial pressure of end-tidal carbon dioxide; vs. =versus

They all demonstrated substantially reduced reliever usage (SABA) and most of them showed increased quality of life, without impairment of lung function (spirometry). Two studies, (4, 6) also showed reduced inhaled corticosteroid usage. Cooper et al. (3) compared the method with placebo and the Pink City Lung Exerciser.

In a non-randomised but controlled study Hassan et al. 107 showed, that BHT increased and peak expiratory flow in one second (PEF 1) improved significantly after BM. The study of Bowler et al. (1) examined therapeutic mechanisms behind the method. They measured lower levels of P ET CO 2 at baseline as compared to the control group. They showed a decrease in pulmonary ventilation (V´ E) after the method, but without changes in P ET CO 2. They also found a correlation between decreased SABA

2 usage and lower levels of V´ E (r = 0, 51). The study of Abramson et al. (5), published as an abstract, reported lower levels of P ET CO 2 and a marginal reduction in the ventilatory response to CO 2 after BM. Courtney et al. 34 , showed a significant correlation between short BHT and a thoracic-dominant breathing

111 pattern, but a negative correlation between P ET CO 2 and BHT. Another research of Cooper et al. demonstrated that mouth-taping without BM had no influence on asthma control in symptomatic asthmatics.

32 Until now, research on BM has not been able to fully support the CO 2 theory. Thomas et al. , support the theory somewhat. They surveyed 210 asthmatic adults using the Nijmegen Questionnaire, a validated questionnaire that differentiates hyperventilation and dysfunctional breathing. They showed that hyperventilation is more common in women and in almost 30% asthmatic adults. Further exploration of the control of respiration and other mechanisms behind the method is needed. 112

Breath holding and the Buteyko method Breath holding competence is an essential part of self-management in BM. BHT is not used for therapeutic purposes. It is not an exercise, but it gives feedback about risk estimations of symptom

9,10 70 recurrence and exacerbation. It is also relevant to the respiratory chemosensitivity of CO 2.

34 Additionally, BHT is shown to have a relation with abnormal spirometry , PACO 2 (Karsten-Voets HMM. unpublished master thesis, 2006), dysfunctional breathing 79 , and hyperventilation.113 Success in BM is evidenced by progressively longer BHT, as chemosensitivity for CO 2 decreases and levels of CO 2 rise. However, only a limited amount of research has been done with BHT.

Breath holding measurements are performed differently by different researchers and can possibly have training effects. 79 Nishino et al. 70 have investigated different methods of BHT and showed different training effects (that is, improvements after successive tests), on two distinct periods in the process of voluntary breath-holding. A first period showed no training effect, and a second period when on-going breath holding indicated a training effect.

The first period of BHT was hardly influenced by the stress of breath-holding and the activity of the respiratory muscles. Precise instructions have to be followed to determine a correct BHT. It is measured while sitting straight, starting after a gentle expiration and lasting until the first desire to breathe again.

This measurement is performed correctly when tidal volume (V T) and frequency (f) are the same before

9 and after breath holding. When breath holding, CO 2 accumulates in the blood . The greater the

ventilatory response to CO 2, the shorter the period of no respiratory sensation during breath holding . A significant correlation between the first breath-holding period and CO 2 chemosensitivity was observed, and this measure was concluded to be useful in studies for clinical testing causes of dyspnea. 70 The BM uses this BHT protocol and is considered fairly standardized. 79 It is mapped in BM and relates to the extent of ventilation dysfunction.9

The second period of ongoing breath holding after the first period was shown to be influenced by physiological and non-physiological factors. It improved with successive trials, showing a training effect.

114 To obtain the ventilatory CO 2 response curve, a rebreathing test using a modified Read’s technique was performed for the two periods separately. These tests showed the first “post-expiratory period of no respiratory sensation” to be below a certain “central threshold of the centrally generated respiratory motor command signal”.70

Reducing ventilation, as done in BM, is concluded to be a reasonable approach to increase asthma control. 115 Still, there is a need for physiological based explanations of the mechanisms behind the positive results of BM.4 Studies with detailed ventilation measures at baseline and after a breathing

7 intervention are proposed. Respiratory chemosensitivity for CO 2 is recommended as one of the primary

7, 115 outcome measures of ventilation. Research has shown that continually reducing V´ E may increase

75 the ventilatory recruitment threshold of PaCO 2 , and the protocol of BHT in BM is a significant indicator

70 for the respiratory chemosensitivity of CO 2.

2 Aims and Objectives

The aim of this study is to assess the effects of BM on resting ventilation and asthma control in a group of asthmatics.

Objectives are to assess the effects of BM on

• Resting ventilation as measured by V’ E, PET CO 2 and P ET O2.

• Perceived asthma control as measured by the ACT and SABA usage.

• Metabolism as measured by V’CO 2 and V’O 2.

• Respiratory chemosensitivity for CO 2 as evidenced by BHT.

3 Methods

This was a prospective, controlled, intervention study with 6-month intervention period.

3.1 Participants We recruited 36 asthmatics from medical centres, the Icelandic Asthma and Allergy Association, general practitioners, and from pulmonary specialists. All the participants were 18 years or older. To be included, the asthmatics had to have a physician diagnosis of asthma. They had to have benefited from SABA use in the four weeks prior to the start of the study. The asthmatics were divided into three groups according to their SABA use: very mild, when SABA usage was less than or once a month (≤ 1/month); mild, when SABA usage was less than once a day (<1/day); and moderate, once a day or more (≥ 1/day). They also had to be willing to participate in BM. In addition, they gave their oral agreement to be prepared to do breathing exercises twice a day. Smokers (2 participants) and ex-smokers (1 participant) were not excluded. Diagnosis of other respiratory diseases, including chronic obstructive pulmonary disease (COPD) (1 participant) and co-morbidities such as depression, GERD, high cholesterol, fibromyalgia and obesity were allowed (see Table 3). To evaluate if the groups were comparable, we paired 20 healthy control participants for gender, age and BMI with 22 asthmatics, who finished the study. The healthy control participants were obtained by approaching friends, family and employees of Reykjalundur. They had no history of obstructive airway disorders as asthma nor dyspnea, they did not use any health related medication and did not know anything about the BM. Smokers were allowed (3 participants). Approval of the National Bioethics’ Committee was obtained before starting this study (see Appendix A, number VSNb2012010044/03.7). The participants received an introduction letter before participating to the study (see Appendix C). Participants were provided with written informed consent forms that they signed in order to participate in this study (see Appendix B).

Table 3. Asthma history and medication usage at M1 Years since Age Steroid and Steroid SABA Gender initial Comorbidity SABA (years) LABA usage usage diagnosis F 41 Childhood Allergy Pulmicort 1/day Bricanyl* 3/day" Depression/ F 45 12 Pulmicort 2/day Ventolin 3/day GERD Fibromyalgia/ F 44 Childhood Flixotide 2/week Ventolin 1/week" Rhinitis M 21 Childhood N n n Ventolin 3/week" F 61 21 Allergy Seretide 1/day Ventolin 3/week F 23 7 n n n Ventolin* 2/day" Obese/ F 42 Childhood Seretide 2/day Ventolin 3/day Rhinitis M 71 26 n Flixotide 1/day Bricanyl* 2/day Fibromyalgia/ F 57 28 Depression/ Seretide 1/day Ventolin 3/week Rhinitis F 61 Childhood Adison disease Dexamethasone 0, 5/day Ventolin 2/day" Obese F 22 Childhood Symbicort 1/day Ventolin 2/day /Fibromyalgia GERD M 38 Childhood Symbicort 3/week Bricanyl 2/day /Blood pressure Mould F 55 Childhood n n Ventolin 2/day /Rhinitis GERD/ F 64 20 n n Ventolin <1/month Rhinitis Depression/ M 40 3 Seretide 1/day Ventolin 2/day GERD M 31 25 n Relvar 1/day Bricanyl 2/day F 33 26 Rhinitis Seretide 1/day Ventolin 3/week" COPD/ F 53 Childhood Chrone’s disease/ Seretide 4/day Ventolin* 1/week" Diabetes Xolair- injections/ F 21 5 Relvar 2/day Ventolin 3/day Rhinitis GERD/ F 56 4 Flixotide 2/day Ventolin* 3/week" Fibromyalgia F 54 Childhood High cholesterol Flixotide n Ventolin 3/week GERD/ M 69 62 Hypertension/ Decortin 1/ day Ventolin* 1/week Rhinitis

n = never; F= female; M = male; COPD= chronic obstructive pulmonary disease; GERD= gastroesophageal reflux disease. * = Nocturnal symptoms 1-2 a week “= Limitation of exercises, SABA use not included

3.2 Protocol Particular emphasis was placed on measuring at complete rest to ensure the least provocation of the central respiratory centers. Measurements described below were taken at the laboratory in Reykjalundur, on the weekends, in the early mornings, and before breakfast. While measuring

ventilation, all participants sat straight and listened to the same relaxing audio. No food, medication, alcohol, caffeine, nor physical activity was allowed at least eight hours before measuring. Measurements were performed in the following order: weight and height, blood pressure and pulse, resting ventilation and metabolism, BHT, spirometry, and the ACT (see Figure 12). Care was taken to make certain that all participants were examined with the same protocols and in the order described. Seasonal influences were taken into account. Measurements of the participants were spread over the year, as asthma symptoms can be triggered by the changing of seasons.

Measures To be able to assess our aim and objectives, the following measurements were taken:

Ventilation at rest, metabolism and spirometry

Measurements of resting ventilation (V’ E), end-tidal carbon dioxide (P ET CO 2), end-tidal oxygen (P ET O2), tidal volume (V T), respiratory rate (RR), carbon dioxide output (V’CO 2) and oxygen consumption(V’O 2), were sampled. This was done while participants were connected to a metabolic cart device (Vmax Encore 29, Sensormedics, CA, USA). They were sitting in a straight position and listened to relaxing audio for 15 minutes while wearing a facemask. The average of the last four minutes of measurements were used for statistics. The ventilatory equivalent for CO 2 output (V’ E ̸ V’CO 2) was calculated. Measures of lung function variables, including FEV 1 and FVC, were made with the same device and were expressed as percentages predicted for gender, age, height, mass, and ethnicity.49

Asthma control

The ACT was used to measure asthma management. 20, 116, 117 (see Appendix D and E). The ACT involves 5 items assessing asthma symptoms (daytime and nocturnal), the use of rescue medications, and the effect of asthma on daily functioning. Each item includes 5 response options corresponding to a 5-point, Likert-type rating scale. Responses for each of the 5 items are summed to yield a score ranging from 5 (uncontrolled asthma) to 25 (controlled asthma). A score > 19 points indicates well- controlled asthma.

Symptoms, SABA use and severity .

Asthmatics had to fill out diary cards (see Appendix F). Diary cards supported the asthmatics in evaluating their asthma and in completing the ACT. They could recognize fluctuations of asthma control by registering symptoms such as coughing, breathlessness, and chest tightness, and by registering waking at night, symptom related restrictions in physical activity, missed school/work days, and visits to their physician or to an emergency department. Symptoms of allergies, medication use, and asthma exacerbations had to be registered on these cards.

Breath holding time protocol

BHT in BM is the time after a normal exhalation until the very first sensation of shortage of air. Participants had to sit straight, and, after a gentle expiration, they had to stop breathing by pinching their nose with mouth closed, until the first desire to breathe again. The measurement was performed correctly, if VT and f were the same before and after holding their breath. BHT measurements were

repeated three times, with one-minute intervals, and the mean was used for statistics. Time measurements were done with a stopwatch that measures 0.01 of a second.

3.3 Procedure Data collection was conducted from June 2012 through January 2016. The asthmatics were measured three times; 6 months before the intervention (M1), just before the beginning of the intervention (M2), and 6 months later (M3). The first period (M1-M2) was the control period for the asthmatics. The control group were measured two times, at M1 and M2 (see Figure 11). Fourteen asthmatics, or 39%, did not finish the study. Five (36%) of them did not attend the BM classes because of personal problems not related to the study, five (36%) dropped out directly after the classes because of a lack of interest in the method, and four (28%) of them tried to keep exercising but resigned as they were unable to follow instructions and do the exercises.

Figure 11. Flowchart of procedure and participants. Measurements were performed for 36 asthmatics. 14 (39%) of them dropped out of the study. The 22 asthmatics left were compared to 20 healthy controls

The asthmatics had to complete the ACT at M1, M2 and M3 and once a month, from M1-M2 (6 times), from M2-M3 (6 times). They also had to fill out diary cards during M1-M2 and M2-M3 (see Figure 12). For examining SABA use at M1, we used their responses to question 4 on the ACT completed at M1. For examination of SABA usage at M3, we calculated the average use of SABA in the two months before M3 from their diary cards, when available. When not available, we used the response to question 4 from their ACT.

Figure 12. Measurements performed for both groups at M1, M2 and M3

The intervention

The asthmatics were taught BM after M2. According to their registrations, 6 groups of 4-7 participants were formed. Instructions of the BM were provided in 5, 2-hour sessions over 3 weeks for each group. The asthmatics were taught the BM by a trained and internationally accredited Buteyko practitioner and physiotherapist. They were taught techniques designed to reduce their breathing direct and indirect, according to components of the method. These included awareness, relaxation, nose- and low tidal volume breathing techniques. Besides other exercises, they received individual management and guidance on how to avoid deep breathing in daily life.

The participants had to train twice a day; once in the mornings and once in the evenings and register BHT on diary cards. 9, 10 Breath holding measures were taken before and after exercises to evaluate both the training and progress. To achieve normal ventilation, BHT set-points had to be assessed with an end goal of 60 seconds. According to BM, physical activity other than walking was not yet advised during the study. To be able to increase physical activity, BHT had to be over 20 seconds. The asthmatics were encouraged to stay on their medication regime, as advised by their physician. If they wished to change their asthma medication, they were advised to discuss this with their physician. Intervention period

The second period (M2-M3) was the intervention period for the asthmatics. The evaluation day for assessing progress and training motivation was in the middle of the intervention period. End measures were taken at the end of the six months intervention period M3, a year after M1 (see Figure 11).

3.4 Statistical analysis Data was entered into a statistical program (StatView) and was checked for any abnormalities or errors. Summary statistics were used to analyse the characteristics of the groups. Descriptive statistics were

used to identify trends in outcomes, as measures of resting V´ E, ACT, spirometry, PET CO 2, BMI, and BHT. We used unpaired students’ t -tests to compare means of measures between groups. Linear regression was used to find a correlation between changes in BHT and PET CO 2. To detect a within patient change from M1 to M2 to M3 for measures of resting ventilation, ACT, spirometry, PET CO 2, BMI and BHT, ANOVA for repeated test was used with Fisher post hoc analysis, to correct for repeated comparisons. To detect changes in control group from M1 to M2, paired t-test was used. To test for differences in changes between the groups from M1-M2 for measured parameters, an unpaired t-test was used. Responses were expressed as mean ± SD. Statistical significance was set at p < 0.05.

4 Results

To evaluate parameters for the 22 asthmatics who finished the study during the control period, their measurements were compared between M1 and M2. To assess if the asthma group was comparable to the healthy control group, we compared measurements of the 22 asthmatics to measurements of the 20 healthy control participants at M1 and at M2 and between M1 and M2. To assess the effects of BM, measurements of the 22 asthmatics performed at M1 and M2 were compared to their measurements at M3. Participants After matching for age, gender, and BMI, there were no significant differences between the asthma and healthy control groups (see Table 4). A rough examination shows dropouts in the asthma group not to be different from those who participated in the study.

Table 4. Measures of age, gender and BMI for all participants at M1 M1 Asthmatics (22) Controls (20) p- value Age (years) 46.1±14.6 45.1±15 NS Gender(F/M) 16/6 16/4 NS BMI 27.9±5.3 26.5±5 NS

BMI = body mass index; F = female; M = male; NS= nonsignificant.

Between M1 and M2, there were no significant differences in or between groups in regards to BMI. Between M1 and M3, the mean of measured BMI had increased in the asthma group (see Table 6).

4.1 Ventilation Between M1 and M2, no differences were found between the groups for the means of the measured parameters of ventilation (see Table 5 and 6). Lung function was in the normal range for both groups, and no significant difference was observed for FEV 1 or FVC. However, the FEV 1/FVC ratio was significantly lower in the asthma group, compared to the control group (see Table 5).

Table 5. Ventilation measurements at M1

M1 Asthmatics (22) Controls (20) p- value

V´ E 6.7±1.7 6.4±1.3 NS

FEV 1(L) 3.06±1.1 3.36±1.0 NS

FEV 1(% pred) 96.6±21.2 105.8±14.1 NS FVC(L) 4.04±1.1 4.20±1.3 NS FVC (% pred) 108.6±17.1 112.3±17.7 NS

FEV 1/FVC 74±1 80±1 0, 04

V´ E = pulmonary ventilation; BHT = breath holding time; FEV 1 = forced expiratory volume in one second; FVC = forced vital capacity; pred. = predicted; L = litre; NS = non-significant

At M3, in the asthma group, the means of measured FEV 1 and FVC decreased, but the ratio of

FEV 1/FVC did not change (see Table 6).

PET CO 2 and PET O2 were measured to examine alveolar ventilation. In the asthma group, significant changes were seen between the means of measures from M1 to M3 and from M2 to M3, as PET CO 2 increased and P ET O2 decreased (see Figure 13).

Figure 13. Partial pressures of end-tidal carbon dioxide (P ET CO 2) and oxygen (P ET CO 2) of the asthma group (blue) versus the control group (blue) at three different time points. Points represent mean values and standard deviations for the asthma group and the control group. *= p<0.05 in M3 versus previous

In the asthma group, the means of measures of V ‘E and VT decreased between M1 and M3, and M2 and M3, but the mean of RR remained the same (see Table 6).

Table 6. Parameters before (M1), after the control period and before intervention (M2), and after intervention period in the asthmatic group (M3) as compared to their controls.

Asthmatics (n=22) Controls (n=20) M1 M2 M3 M1 M2

BMI 27.9±5.3 28.3±5.5 28.7±5.9 * 26.5±5 26.4±5.1

FEV 1 (% pred.) 96.6±21.2 99.05±19.5 93.8±18.2 * 105.8±14.08 105.2±14.34 FVC(% pred.) 108.6±17.1 109.9±18, 1 104.5 * 112.3±17.67 112.2±19 ¥ FEV 1/FVC 74±1 75±1 75±1 80±0.7 80±0.7

V‘O 2 L/min 0.180±0.07 0.187±0.06 0.146±0.06 * 0.191±0.06 0.196±0.05

V‘CO 2 L/min 0.148±0.06 0.16±0.06 0.118±0.05 * 0.152±0.05 0.153±0.04

V´ E L/min 6.65±1.74 6.88±2.00 5.69±1.70* 6.38±1.3 6.43±1.4

VT(L) 0.58±0.21 0.68±0.27 0.49±0.16* 0.67±0.27 0.66±0.18 RR(per minute) 12.2±2.7 11.1±2.9 12.2±3 10.9±3.5 10.7±2.9

V‘ E/V‘CO 2 48.3±10.5 44.4±7.7 52.2±13.3 * 43.9±9.9 43.3±7.8

FEV 1 = forced expiratory volume in one second; FVC = forced vital capacity; pred. = predicted; V’O 2 = oxygen consumption; V´CO 2 = carbon dioxide output; V´ E = pulmonary ventilation, VT = tidal volume, RR = respiratory rate, V’ E/V’CO 2 = ventilatory equivalent for carbon dioxide. * = p<0.05 in M3 versus previous measurements, ¥ = p<0.05 in control versus asthmatics.

4.2 Asthma control To interpret asthma control, scores from the ACT were examined. At M1 and M2, the asthmatics were not well controlled, with mean scores of 16.7 and 18.6 respectively. At M3, the mean score was 21.3, indicating well-controlled asthma (see Figure 14).

Figure 14. Results from the ACT. Bars represent mean values of scores with standard deviations. Scoring > 19 points indicates well-controlled asthma. * = p<0.05 in M3 versus previous measures.

The number of asthmatics with SABA usage ≤ 1/month, or very mild, increased from 1 to 14. Participants from the asthma group with SABA usage < 1/day, or mild, decreased from 9 to 7. The subgroup with usage ≥ 1/day, or moderate, decreased from 12 to 1 (see Figure 15). This is calculated to an 85% drop in SABA usage in the 22 asthmatics. Precise measures of combinations of LABA and inhaled and/or oral corticosteroids were not performed in this study, but an estimation indicated a decrease of 45%.

Figure 15. SABA usage before and after the Buteyko method. Number of participants according to their SABA use before and after BM . Very mild = ≤ 1/month; mild = < 1/day ; moderate = ≥ 1/day.

4.3 Metabolism

To be able to evaluate metabolism, measures of VÓ2 and VĆO2 were examined. Between M1 and M2, the means of these measures did not show differences between the groups (see Table 6). At M3, the means of measured VÓ 2 and VĆO 2 decreased. As these metabolic measures decreased more than

V´ E after the intervention (p < 0.05), values of V’ E/V’CO 2 increased significantly between M2 and M3. (see Table 6).

4.4 Breath holding time

BHT was measured to evaluate respiratory chemosensitivity for CO 2. At M1 and M2, the results showed that the asthma group had significantly shorter BHT than the control group. At M3, the mean of BHT measures became longer in the asthmatic group (see Figure 16).

Figure 16. Breath holding time measures for the asthma group (blue) versus the control group (orange), at three different time points. Points represent mean values and standard deviations for the asthma group and the control group. ¥ = p<0.05 in control group versus asthma group; ¤ = p<0.0001 M3 versus previous measure .

The correlation for changes of measured BHT and P ET CO 2 was evaluated. A significant correlation was found when one extreme case with highly variable P ET CO 2 and BHT levels was excluded. This case was taken out, as the cause of these extreme values could have been a high dosage of oral steroid use

2 at M2. The coefficient of determination between the changes in BHT and changes in PET CO 2 was r = 0, 2772, p<0.02 (see Figure 17).

Figure 17.∆ BHT Line Fit Plot without extreme case. A significant correlation was found for changes 2 in BHT and P ET CO 2 when the extreme case was excluded (r = 0.2772, p<0.02).

In summary, the effects of BM were visible in changed means of measures of resting ventilation, higher levels of P ET CO 2, lower levels of P ET O2, together with increased asthma control and reduced respiratory chemosensitivity for CO 2 in asthmatics.

5 Discussion

The results showed no difference in resting ventilation in asthmatics at baseline as compared to their healthy controls. However, BHT among the asthmatics was shorter before BM, indicating higher respiratory chemosensitivity for CO 2. Values of BHT were longer after BM, which is in accord with lower respiratory chemosensitivity for CO 2. Higher values of P ET CO 2 and lower values of PET O2 were measured after BM, indicating decreased values of V´ A/V´CO 2. Both V´ E and metabolism decreased after the intervention, the latter more than the former, resulting in increased V´ E/V´CO 2. Higher values of

V´E/V´CO 2 and PET CO 2 and lower values of P ET O2 implied more dead space ventilation, due to changes in breathing patterns, i.e., lower V T. Asthma was not-well controlled before, but well controlled after, BM.

Lung function measures such as FEV 1 and FVC decreased, but their ratio stayed the same after the intervention.

5.1 Pre-intervention Ventilation was examined at utmost rest in our participants, with the least provocation of respiratory control. In these conditions, no marked increase in ventilation is shown in the asthma group. Increased ventilation is expected from past studies and from the theory of the BM. 39, 45, 60, 118, 119 Thomas et al. 32, 39 tried to evaluate hyperventilation in asthmatics using the Nijmegen questionnaire (NQ) 120 , a validated screening tool to distinguish people who hyperventilate from people who do not.38 They reported that one third of asthmatic women and one fifth of asthmatic men had symptoms associated with hyperventilation or dysfunctional breathing. 39 Bowler et al. 55 confirmed significantly lower levels of

PET CO 2 at rest in asthmatics as compared to a normal group, without evidence of clinically increased breathing. In a controlled study of 23 mild and stable asthmatics, Osborne et al. 60 reported significant lower levels of P ET CO 2 and PaCO 2 at rest in asthmatics, compared to healthy controls. Still, they could

not show clinically significant hyperventilation. It is difficult to understand the exact reasons for these findings as they did not measure metabolism. Also, as Osborne et al. themselves noticed, measures were taken with a mouthpiece and nose clip, which could have influenced breathing. 121 Furthermore, it may be argued whether patients were measured at complete rest in the study of Osborne et al. Although participants were not allowed to use caffeine nor bronchodilators eight hours before measuring, other features could have influenced their ventilation such as emotional state, recent physical activities, food intake, and posture. 122, 123 In our study, by measuring in protocolled optimal resting circumstances, with the least physical and psychological challenges, we tried to normalize conditions pertinent to the disease and reduce variability that could contribute to our findings for both groups. Hormbrey et al. 45 examined breathing patterns in symptomatic asthmatics, in people with symptoms of hyperventilation and in healthy subjects. At rest, the asthmatics had significantly higher V´ E and lower levels of P ET CO 2 (37 mmHg), compared to people who were supposed to hyperventilate (40 mmHg) and healthy subjects (41 mmHg). However, there were only 6 participants in each group. In this study, hyperventilation was

41 related to changes in CO 2 levels rather than long-term CO 2 levels. William N. Gardner explained that voluntary hyperventilation can result in a drastic removal of alveolar CO 2 (P ACO 2), primarily coming from alveolar gas, then from blood in pulmonary veins, from the left side of the heart, and, finally, from the first part of systemic circulation. Hence, a few minutes after hyperventilating, partial pressure of PACO 2 had returned to normal. A new balance had been achieved between a wash-out from the lungs and the tissues with same P ACO 2 levels, corresponding to “a 50% change of CO 2 content of the body tissues

115 61 with a change of 5 minutes in P ACO 2”. The reviews of Bruton et al. and Meuritz et al. have shown asthmatics to have a tendency of lower levels of PaCO 2, compared to healthy subjects. Also, Dr. Konstantin Buteyko, who developed the BM, claimed that hidden hyperventilation is one of the causes of asthma. The primary goal of BM is to decrease ventilation, balance it with metabolism, thereby raising

9 levels of CO 2. Hence, other factors need to be sought to explain the theory of the BM.

Asthma in the study subjects was not-well controlled at baseline, according to the mean scores from the ACT. This finding is somewhat similar to the results of the study of Demoly et al. 25 , where they also used the ACT to evaluate asthma control. They concluded that asthma was not well controlled in more than half of the treated asthmatics in 5 countries in Europe. Furthermore, Papaioannou et al. 24 explained that, world-wide, asthma is only controlled in a small percentage of patients. Most of the asthmatics in our study were asymptomatic during the measurements, but they were symptomatic during the study. The severity of their symptoms during the M1-M2 period varied widely. As their SABA use varied from once a month to more often than once a day, they were divided in three subgroups, corresponding with very mild (≤ 1/month), mild (< 1/day) to moderate (≥1/day) SABA use, according to the study of Osborne et al. 60 At baseline, 4.5% were very mild, 41% were mild, and 54.5% were moderate.

The mean values of FEV 1/FVC were lower for the asthmatics in our study, confirming decreased lung function as compared to the healthy control group. Ventilation per metabolism (V’ E/V’CO 2) was higher for the asthmatics in our study, but not significantly so. These differences of V’ E/V’CO 2 between asthmatics and the healthy control group may have become clearer with a larger number of participants.

BHT for the asthmatics was shorter (14.1± 8.2 sec, p< 0.05), compared to the healthy controls, (19± 7.1 sec). According to Nishino et al. 70 , shorter BHT is related to increased dyspnea and greater

respiratory chemosensitivity for CO 2. The longer the breath can be held, the better the accumulation of

CO 2 is tolerated, the lower respiratory chemosensitivity for CO 2. This result conforms to the results in the review of Hida et al.78 , where they indicated that the ventilatory drive in asthmatics is affected by respiratory chemosensitivity for CO 2. They also showed in this review, that the ventilatory drive is related to asthmatics with both a decreased sensation of dyspnea (as in asthmatics who have experienced near fatal asthmatic periods) and an increased sensation of dyspnea (as in asthmatics who did not have experienced near fatal asthmatic periods). They concluded that the ventilatory drive has a fundamental role in determining the severity of asthma . Also, Kassabian et al.77 showed an increased respiratory chemosensitivity for CO 2 in asthma . Still, in their study PET CO 2 and P ET O2 were similar to the control group at baseline, showing no evidence of increased V´ A at rest. In literature, it is suggested that P ET CO 2 can be normal in people with symptomatic hyperventilation at rest.40 Han et al. 89 , did not find changes of P ET CO 2 at rest for people suffering from hyperventilation and anxiety, as compared to people who did not had those issues. They characterized people who hyperventilate as having a respiratory control system that is more sensitive to provocation and with unstable breathing patterns. Macnutt et al. 124 showed chemosensitivity for CO 2 to be higher in women than in men.

It is an attractive proposition to hypothesize that the asthmatics with shorter BHT in this study have an inefficient or dysfunctional way of breathing; the underlying central respiratory rhythm will regenerate quicker but only when provoked, resulting in more quickly increased ventilation as when symptomatic.

Increased ventilation decreases levels of PaCO 2 and triggers dyspnea sooner compared to subjects

62, 75 with longer BHT. Furthermore, the relation between levels of PET CO 2 and bronchodilation/- constriction is well known in physiology 49 and this relation is confirmed by experimental studies of O´Cain et al. 125 , van den Elshout et al. 91 and other studies.47, 61, 91

5.2 Post-intervention This study evaluated the effect of the BM on resting ventilation and asthma control in asthmatics. Our findings showed that asthmatics had retrained their breathing patterns without any study-related adverse effects. At M3, the asthmatics had become more aware of their breathing and had avoided deep breathing. Some had even experienced changes in their breathing patterns, such as being aware of greater breath suspension episodes in daily life, indicating slower RR. However, our data showed no significant change in RR, but a significant change in V T. This is consistent with the study of Wolkove et al. 74 , when they investigated the physiology of ventilation during transcendental meditation (TM) as a relaxation method. Their results showed minute volume (V’ E) to decrease due to a decreased tidal volume (V T). In their study, VT was smaller at same levels of P ET CO 2 compared to controls, and these findings were associated with the chemical and neural regulation of ventilation. Our data also showed increasing levels of PET CO 2 together with decreasing levels of P ET O2. According to physiology, these

55 are indicators of lowered values of V´ A in relation to V´CO 2. Bowler et al. showed reduced V´ E after BM (14 ± 6.5 versus 9.6 ± 3.1 L/min), but without measuring metabolism and with unchanged low levels of

105 47 PET CO 2. Abramson et al. were able to show increased P ET CO 2 levels after BM. Ritz et al. showed higher levels of P ET CO 2 after a capnometry assisted respiratory training (CART), but not after slow breathing and awareness training (SLOW). These trainings were not according to the BM, but they were

based on the hypothesis that raised levels of CO 2 could increase asthma control. Still, subjects in both studies increased asthma control, implying that the results only partially supported the hypothesis that

CO 2 is related to asthma control.

Asthma was well-controlled after the BM, as average scores for the ACT reached above the set-point of 19. In the BM, asthmatics were not encouraged to diminish their medication usage unless advised by their physician. They were instructed to use the BM techniques before using rescue medication. Asthma control increased in all other research that investigated the effectiveness of the method. 21, 55, 81, 106, 108, 109, 126 In our study, after BM, SABA usage had decreased for 85% of the participants. Of those, 63.6% were with very mild, 31.8% were with mild and 4.6% with moderate SABA usage. Bowler et al. 55 also

2 showed a reduction of SABA usage and found a correlation with reduced V´ E, r = 0, 51 p < 0.004.

Although FEV 1 and FVC decreased significantly for the asthmatics, the FEV 1/FVC ratio remained the same after BM. These results resembled the results from Fenger et al. 65 , where they concluded changes of adiposity altered levels of FEV 1 and FVC, but values for the FEV 1/FVC ratio stayed the same.

Metabolism in the asthmatics had reduced at M3, as both values of V’O 2 (0.180 ± 0.07 vs. 0.146 ± 0.06

L/min; p < 0.05) and V’CO 2 (0.148 ± 0.06 vs 0.118 ± 0.05 L/min; p < 0.05) had decreased. The results also showed that asthmatics gained weight at M3 as compared to M1. It can be assumed that these findings are correct as metabolism remained the same in M1-M2 for both groups. A possible explanation

84-86 for asthmatics gaining weight could be decreased SABA or B2-agonists usage. Studies have confirmed metabolic side effects of B 2-agonists in asthma and have suggested these to increase the metabolic rate in asthmatics. Agha et al. concluded that asthmatics have higher basal metabolic rates

84 than normal subjects. Less B 2-agonist usage could possibly have caused weight gain, however slight, in our study. Increased asthma control and decreased SABA usage was accomplished by reduced breathing according to our results. The study of Wallace et al. 83 showed that meditation reduced metabolic rates. Other studies examining meditation and relaxation therapies have shown a shift from sympathetic to parasympathetic dominance in the ANS, together with reduced breathing. 71-74 In addition

127 to this, Matsumoto et al. concluded that the bronchodilation effect of B 2-agonist medication is through activation of the sympathetic nervous system. For these reasons, it is suspected that the nervous system has an impact on the weight gaining effect of reduced breathing and reduced B2-agonist usage.

V’ E decreased, but when we corrected V’ E for metabolism, we found an increase in values of

V’ E/V’CO 2 (44.4 ± 7.7 vs. 52.2 ± 13.3; p < 0.05) after BM. Although both V´ E and metabolism decreased,

V´ E decreased less than metabolism. At the same time values of P ET CO 2 increased and PET O2 decreased, which is considered supportive for lower values of V’ A/CO 2. Higher values of V’ E/V’CO 2 and estimated lower values of V’ A/CO 2 after BM, indicate that more energy is wasted in dead space ventilation. An explanation could be that these changes are derived from a decline in V T, without changes of RR. The percentage of breathing lost in dead space ventilation (V´ D) increases when V T decreases. In this phase of BM, it could be said that the asthmatics (still) breathe ineffectively or dysfunctionally. They are in the middle of changing their breathing patterns and life style. They still have a long way to go to reach the 60-second BHT end-goal of BM, and reducing their RR will very likely be a part of it.

In this study, asthmatics reached the BHT set-point of 20 seconds at M3 (25 ± 8.7 sec). These measures became similar to measurements from the control group (21.5 ± 11.3 sec). They were similar to measurements from BHT (13.4 ± 5.19 vs. 22.67 ± 7.38, p < 0.0005) after BM in the study of Hassan et al. 107 , when they examined BM on patients with bronchial asthma. Our study presented a positive,

2 significant correlation for the changes in BHT and P ET CO 2. The coefficient of determination (r ) between

2 the changes in BHT and the changes in PET CO 2 is r = 0, 2772, p< 0.02 , indicating that almost 30% of higher levels of P ET CO 2 were due to less respiratory chemosensitivity for CO 2, as evidenced by higher BHT. According to Ninisho et al. 70 , this implicated less dyspnea. In the context of these results, it could be said that breathing less means less breathlessness.

Our results could be considered supportive for the theory of the BM in that they provides evidence that confirms reduced breathing to increase asthma control. Higher levels of PET CO 2, lower levels of

PET O2, together with increased asthma control may be fundamental to the pathophysiology of asthma.

BM, apparently, reduced the chemosensitivity for CO2 and this might have taken away the underlying causes of asthma. This study also indicated that breathing patterns may be altered and that the steady state of ventilation can be reset.

There were undoubtedly nonspecific intervention and professional attention effects that could cause spontaneous improvements of symptomatic asthmatics, as mentioned in Gina16 and other studies.4, 98, 112 Factors such as relaxation, self-efficacy, and voluntary reduce of medication could partially have caused the results of the intervention. The techniques used in the BM gave the asthmatics a feeling of control, reducing their anxiety about their symptoms. The BHT in BM gave asthmatics information about their progress and results, and improvements might have enhanced their self-efficacy. 21, 46, 81, 109

5.3 Strength and limitations Complex interventions like these were methodologically difficult to control. Our design of comparing an asthmatic group to themselves as their own control group and comparing them to healthy participants provided a credible control procedure. Therefore, our results can be related to aspects of the intervention.

We examined asthma control and ventilation at rest in people with asthma who found relief from medication. Our most important preselection was that the asthmatics had to have benefited from the use of rescue reliever medication in the last month. We measured in protocolled optimal resting circumstances, with minimal physical and psychological challenges. We tried to normalize conditions pertinent for the disease and reduced variability that could contribute to our findings for both groups. We tried to assess seasonal effects involving different risk factors on asthma by measuring the groups at different times of the year. Allergies in summertime and cold dry air in wintertime are the most observed triggers in this study. The BM was unknown in Iceland, and it was possible that asthmatics could have found information about the method on the internet or elsewhere, as it was mentioned in our advertisements for participants.

Limitations

Although a sample size of 20 participants in each group was statistically predicted to be sufficient, bigger sample sizes would have given even more reliable results.

Having more asthmatics participate in the study and randomising them for a BM group and an untreated group would have made the study a randomised trial. Finding asthmatics willing to participate was difficult, and this would have taken too long time. The BM is a complemental treatment to initial treatment strategies, according to guidelines of asthma management. Physicians and lung specialists in Reykjavík were informed about the BM, but it was difficult to encourage them to help us to find the right participants. Only two of the subjects had been encouraged by their physician to participate in this study, but most of the participants had seen recruitment material in pharmacies or medical centers. The Buteyko method is still unknown on Iceland and, one could say, revolutionary. That could be one of the reasons why it was difficult to find participants in a small society like Iceland. Further on, it would have been appropriate for the researcher to inform the family physicians of the asthmatics of their participation in the study to keep the physicians informed.

We have not been able to assess hyperventilation or dysfunctional breathing in our asthmatics with the Nijmegen Questionnaire, 38 as this questionnaire has not yet been translated into Icelandic and tested in Iceland. The inclusion criteria of benefitting from SABA use in the last month was subjective. It would have had more significance if benefitting from SABA was confirmed in lung function testing. Also, it would have been interesting to examine psychiatric disorders such as depression and anxiety assessments. Other studies have evaluated psychiatric disorders and suggested a relationship between anxiety, depression, and asthma control.29, 60 This could have contributed to the examination of who benefits the most from these breathing methods.

As nasal breathing is emphasized, it is likely to have affected NO levels in our participants. NO is produced in many cells in the body and also in the endothelium of the paranasal sinuses. NO is involved in a large number of physiological processes; it has both local effects such as host-defence by keeping the nasal sinuses sterile, and distal effects such as bronchodilation, vasodilatation, improving

50, 128 ventilation/perfusion matching, O2 transport, and immune responses.

A considerable number of participants dropped out of the study, or 14 (39%) of the 36 asthmatics. This was not unexpected as participation required a long-term commitment of the participants. The intervention was complex, involving lifestyle changes and most participants were in their forties. These could be important limitations, as young people might change their lifestyles more easily. The two youngest people in our study, 19 and 21 years old, demonstrated significant positive results shortly after the intervention. Further explanations could be that participants did not pay for the Buteyko method, nor were they rewarded in any way. The method is unknown, revolutionary and not encouraged by physicians and this could have an influenced their enthusiasm in compliance with exercising.

Actual compliance with the daily exercises and diary cards was not closely monitored. These trainings require considerable commitment from the individual patients, in terms of time and effort. The BM is best suited to people who do not want a quick fix, are not content with medication use, and are prepared to change life habits. The belief in therapy efficacy grew among the asthmatics who completed the study, in response to experiencing improvements in their condition. All of the 22 participants reached the 20-second set point of BHT.9, 10 To reach the 60-second end-goal of the BM, longer follow ups are required. Then, physical exercise would also become part of the instructions.

5.4 Future studies Asthma diagnose involves a variety of phenotypes. Different therapies may be effective for different people, and it is not known who benefits most from breathing exercise methods. This study has not approached this knowledge. Further investigations with breathing methods such as BM are needed. Longer follow ups are preferable, at least until the BM end-goals are reached for each participant. A measure of commitment for being prepared to train breathing should be one of the criteria included. Also, measurements evaluating inflammatory biomarkers, bronchial reactivity, and hyperventilation assessments, with questionnaires such as the Nijmegen questionnaire 38 , and blood gas tests are preferable. This is important for correctly diagnosing and targeting who (according to personality and breathing style) would benefit most. It would be interesting to investigate the method with children. Two studies with children have been done and have shown excellent results.129, 130 Studies with severe asthma offer interesting options to examine whether severe asthmatics can obtain better control with the method. One study 131 examined BM and physical exercise and another is on-going in Germany. It would be important to investigate if, and what type of asthmatic, hyperventilates during physical exercise, by examining blood gases. All this is crucial in assuring that the method will become a responsible and cost-effective part of overall asthma management.

6 Conclusion

In summary, this study provided detailed information about the physiology of ventilation at rest and asthma control in asthmatics, before and after the Buteyko method. This study showed no evidence of dissimilar ventilation or P ET CO 2 at baseline, when measured at utmost rest, compared to a healthy control group. Asthma was well-controlled after the method, as evidenced by scores from the ACT. Symptoms decreased and medication use reduced: SABA use by 85% and a combination of LABA/steroid use was reduced by approximately 45%. The study suggested that asthmatics have greater respiratory chemosensitivity to CO 2, as evidenced by shorter BHT. V´ E, chemosensitivity and metabolism at rest decreased after BM, but V´ E/CO 2 increased. Values of PET CO 2 increased and values of V´ E and PET O2 decreased, indicating decreased values of V´ A/CO 2 after the BM . As the distance between estimated V´ A/CO 2 and V´ E/CO 2 increased after BM, it may be concluded that dead space ventilation also increased. Increased dead space ventilation is assumed to be a result of decreased tidal volumes. Measures of lung function as FEV 1 and FVC decreased, probably because of lower metabolic rates, but their ratio (FEV 1/ FVC) remained the same.

In this study, we have tried to give information about the plasticity of chemical ventilatory control and we suggested the BM to have affected the underlying pathophysiology of asthma without disturbing lung function. These results could be important for evaluating therapies for asthma and influencing public health regimes for the management of asthma. Still, asthma is often poorly controlled, despite broadly endorsed management guidelines. It is important for physiotherapists to be able to offer asthmatics a scientifically based and acknowledged 103 breathing exercising method. SABA usage diminished enormously. Since medication costs for asthmatics are increasing and safety profiles of these medications have come under scrutiny, adequate usage and reduction of medication implies a

pharmacy-economic benefit for asthmatics and Iceland. These results could also encourage clinicians to offer qualified, physiotherapy support to patients with asthma for better control of their asthma.

Breathing less means less breathlessness.

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125. O'Cain CF, Hensley MJ, McFadden ER, Jr., Ingram RH, Jr. Pattern and mechanism of airway response to hypocapnia in normal subjects. J Appl Physiol Respir Environ Exerc Physiol 1979;47:8- 12.

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Appendix A

Appendix B

FYLGISKJAL 3a

Vegna vísindarannsóknarinnar

„Hvernig hefur öndun áhrif á einkenni og stjórnun astma sjúkdómsins?“

Samþykkisyfirlýsing fyrir þátttakendur með astma.

Markmið og tilgangur rannsóknarinnar er að kanna hvort og hvernig Buteyko öndunarmeðferð hafi áhrif á einkenni og stjórnun á astmasjúkdómnum. Meðferðin byggir á því að með öndunaræfingum sé hægt að minnka astmi einkenni og lyfjanotkun. Niðurstöðurnar geta verið gagnlegar fyrir bættan skilning á astmasjúkdómnum. Þátttaka í rannsókninni felur í sér að taka þátt í öndunarmeðferð í hópi og halda áfram reglubundnum æfingum samkvæmt leiðbeiningum í allt að sex mánuði. Jafnframt að halda dagbók um lyfjanotkun og líðan. Þátttakan felur einnig í sér að mæta alls þrisvar sinnum í mælingar á Reykjalund á árs tímabili, sem taka um hálfa klukkustund í senn. Ég staðfesti hér með undirskrift minni að ég hef lesið upplýsingarnar um rannsóknina sem mér voru afhentar, hef fengið tækifæri til að spyrja spurninga um rannsóknina og fengið fullnægjandi svör og útskýringar á atriðum sem mér voru óljós. Ég hef af fúsum og frjálsum vilja ákveðið að taka þátt í rannsókninni. Mér er ljóst að þó ég hafi skrifað undir þessa samstarfsyfirlýsingu, get ég hætt þátttöku hvenær sem er án útskýringa og án áhrifa á þá læknisþjónustu sem ég á rétt á í framtíðinni. Mér er ljóst að rannsóknargögnum verður eytt að rannsókn lokinni og eigi síðar en eftir 5 ár frá úrvinnslu rannsóknargagna.

______Dagsetning

______Nafn þátttakanda

Undirritaður, starfsmaður rannsóknarinnar, staðfestir hér með að hafa veitt upplýsingar um eðli og tilgang rannsóknarinnar, í samræmi við lög og reglur um vísindarannsóknir.

Undirskrift:______

Dagsetning:______

FYLGISKJAL 3b

Vegna vísindarannsóknarinnar

„Hvernig hefur öndun áhrif á einkenni og stjórnun astma sjúkdómsins?“

Samþykkisyfirlýsing fyrir þátttakendur í samanburðarhópi.

Markmið og tilgangur rannsóknarinnar er að kanna hvort og hvernig Buteyko öndunarmeðferð hafi áhrif á einkenni og stjórnun á astmasjúkdómnum. Niðurstöðurnar geta verið gagnlegar fyrir bætann skilning á astmasjúkdómnum. Þátttaka í rannsókninni felst í því að mæta í mælingar tvisvar sinnum á Reykjalund með 6 mánaða millibili. Hvor heimsókn tekur hálfa klukkustund og er þátttakanda að kostnaðarlausu. Ég staðfesti hér með undirskrift minni að ég hef lesið upplýsingarnar um rannsóknina sem mér voru afhentar, hef fengið tækifæri til að spyrja spurninga um rannsóknina og fengið fullnægjandi svör og útskýringar á atriðum sem mér voru óljós. Ég hef af fúsum og frjálsum vilja ákveðið að taka þátt í rannsókninni. Mér er ljóst að þó ég hafi skrifað undir þessa samstarfsyfirlýsingu, get ég stöðvað þátttöku mína hvenær sem er án útskýringa og án áhrifa á þá læknisþjónustu sem ég á rétt á í framtíðinni. Mér er ljóst að rannsóknargögnum verður eytt að rannsókn lokinni og eigi síðar en eftir 5 ár frá úrvinnslu rannsóknargagna.

______Dagsetning

______Nafn þátttakanda

Undirritaður, starfsmaður rannsóknarinnar, staðfestir hér með að hafa veitt upplýsingar um eðli og tilgang rannsóknarinnar, í samræmi við lög og reglur um vísindarannsóknir.

Undirskrift:______

Dagsetning:______

Appendix C

FYLGISKJAL 2a

Upplýsingar vegna vísindarannsóknar.

„Hvernig hefur öndun áhrif á einkenni og stjórnun astma sjúkdómsins?“

Ábyrgðamaður rannsóknarinnar er : Dr.Marta Guðjónsdóttir, lífeðlisfræðingur, lektor við Læknadeild Háskóla Íslands og rannsóknastjóri á Reykjalundi. Sími: 8679890 Tölvupóstfang: [email protected]

Aðrir rannsakendur eru: Monique van Oosten, sjúkraþjálfari, Buteykoþjálfari og meistaranemi í lýðheilsuvísindum. Sími: 8998456. Tölvupóstfang: monique@centrum Kæri viðtakandi.

Rannsóknin „Hvernig hefur öndun áhrif á einkenni og stjórnun astma sjúkdómsins“ er meistaraverkefni Monique van Oosten sjúkraþjálfara við námsbraut í Lýðheilsuvísindum við Læknadeild Háskóla Íslands. Leiðbeinandi hennar er Dr. Marta Guðjónsdóttir. Þér er boðið að taka þátt í rannsókninni þar sem þú hafðir samband við Monique í framhaldi af auglýsingu. Tilgangur rannsóknarinnar er að kanna hvort og hvernig öndunarmeðferð (Buteyko) hafi áhrif á einkenni og stjórnun á astmasjúkdómnum. Buteyko öndunarmeðferðin er viðurkennd meðferð, hún hefur sýnt mjög góðan árangur og stangast ekki á við hefðbundnar meðferðir. Meðferðin byggir á því að með öndunarmeðferð sé hægt að minnka astmaeinkenni og lyfjanotkun.

Þér er boðin að taka þátt ef þú ert 18 ára og eldri, hefur greinst með astma sjúkdóminn, hefur haft þörf fyrir stuttverkandi berkjuvíkkandi lyf eins og Ventolin, einu sinni í viku eða oftar undanfarnar fjórar vikur og ert tilbúin að taka þátt í meðferð og stunda öndunaræfingar reglulega. Ekki verður greitt fyrir þátttöku en mælinga og meðferð verður þáttakendum að kostnaðarlausu. Ef þátttakandi óskar þess munu rannsakendur senda lækni viðkomandi niðurstöður mælinganna sem gerðar eru.

FYLGISKJAL 2a

Í hverju felst þátttakan? Þátttaka varir í 12 mánuði og gert er ráð fyrir: ° Þremur heimsóknum á Reykjalund, endurhæfingarmiðstöð SÍBS með 6 mánaða millibili. Hver heimsókn tekur um það bil 30 mínútur þar sem mæld verður öndun, blóðþrýstingur, hæð og þyngd. Því til viðbótar eiga þátttakendur að fylla út spurningarlista um astma með fimm spurningum sem tekur um 5-10 mínútur að svara. Lyfjanotkun verður skráð. ° Þátttöku í 8-9 manna hópi sem mætir í 5 skipti í öndunarmeðferð, í 2 klukkustundir í senn á tveggja og hálfs vikna tímabili. Eftirfylgd verður eftir þrjá mánuði til að meta árangurinn. Hugmyndafræði og Buteyko öndunaræfingar verða kenndar og gert er ráð fyrir að þátttakendur stundi æfingar heima í 15 til 30 mínútur daglega. ° Að halda dagbók um líðan og lyfjanotkun. Monique van Oosten mun veita frekari upplýsingar í síma eða tölvupósti um meðferðina ef þörf krefur allt rannsóknartímabilið. Áhætta og ávinningur: Áhætta af þátttöku er engin en beinn ávinningur er fyrir þátttakendur þar sem mjög góð reynsla er af öndunarmeðferðinni þar sem vísindarannsóknir benda til að meðferðin minnki verulega þörf astmasjúklinga fyrir lyf og auki lífsgæði þeirra. Auk þess fá þátttakendur mælingar sér að kostnaðarlausu. Niðurstöðurnar af rannsókninni geta verið gagnlegar fyrir bættan skilning á astmasjúkdómnum og meðferð við honum. Rannsókn þessi er gerð með samþykki Vísindasiðanefndar og hún hefur verið tilkynnt Persónuvernd. Aðgengi að rannsóknargögum : Allar upplýsingar sem þátttakendur veita í rannsókninni, verða meðhöndlaðar samkvæmt ströngustu reglum um trúnað og nafnleynd og farið að íslenskum lögum varðandi persónuvernd, vinnslu og eyðingu frumgagna. Í tölfræðilegum úrvinnsluskrám koma ekki fram nöfn og kennitölur þátttakenda heldur fær hver og einn sitt númer sem ábyrgðamaður heldur einn skrá yfir. Rannsóknargögn verða varðveitt á öruggum stað hjá ábyrgðarmanni á meðan á rannsókn stendur og öllum gögnum verði eytt að rannsókn lokinni. Þér er ekki skylt að taka þátt í rannsókninni og þú getur hætt við þátttöku hvenær sem er, án frekari útskýringa. Afstaða þín mun ekki hafa áhrif á þá þjónustu heilbrigðiskerfisins sem þú kannt að þurfa í framtíðinni.

Frekari upplýsingar: Ef þú hefur áhuga að taka þátt í rannsókninni eða fá frekari upplýsingar, vinsamlegast hafðu samband við Monique van Oosten, sjúkraþjálfara í síma 8998456

Með von um góða undirtektir,

Dr. Marta Guðjónsdóttir, lektor og ábyrgðarmaður rannsóknarinnar. Monique van Oosten, sjúkraþjálfari, Buteykoþjálfari og meistaranemi í lýðheilsuvísindum. ______

Ef þú hefur spurningar um rétt þinn sem þátttakandi í vísindarannsókn eða vilt hætta þátttöku í rannsókninni getur þú snúið þér til Vísindasiðanefndar, Hafnarhúsinu, Tryggvagötu 17, 101 Reykjavík. Sími: 551-7100, fax: 551-1444, tölvupóstfang: [email protected].

FYLGISKJAL 2b

Upplýsingar vegna vísindarannsóknarinnar:

„Hvernig hefur öndun áhrif á einkenni og stjórnun astma sjúkdómsins?“

Ábyrgðamaður rannsóknarinnar er : Dr.Marta Guðjónsdóttir, lífeðlisfræðingur, lektor við Læknadeild Háskóla Íslands og rannsóknastjóri á Reykjalundi, Sími: 8679890 Tölvupóstfang: [email protected]

Aðrir rannsakendur eru: Monique van Oosten, sjúkraþjálfari, Buteykoþjálfari og meistaranemi í lýðheilsuvísindum. Sími: 8998456. Tölvupóstfang: monique@centrum

Kæri viðtakandi.

Rannsóknin, Hvernig hefur öndun áhrif á einkenni og stjórnun astma sjúkdómsins“ er meistaraverkefni Monique van Oosten sjúkraþjálfara við námsbraut í Lýðheilsuvísindum við Læknadeild Háskóla Íslands. Leiðbeinandi hennar er Dr. Marta Guðjónsdóttir. Þér er boðið að taka þátt í rannsókninni þar sem þú hafðir samband við Monique í framhaldi af auglýsingu.

Tilgangur rannsóknarinnar er að kanna hvort og hvernig öndunarmeðferð (Buteyko) hefur áhrif á einkenni og stjórnun á astmasjúkdómnum. Þér er boðin að taka þátt ef þú ert 18 ára og eldri, hefur ekki greinst með astma sjúkdóminn, notar ekki heilsutengd lyf og hefur ekki tekið þátt í öndunarmeðferð eins og Buteyko meðferðinni.

FYLGISKJAL 2b

Þátttaka felst í tveim heimsóknum á Reykjalund, endurhæfingarmiðstöð SÍBS, með 6 mánaða millibili, þar sem hver heimsókn tekur um það bil 30 mínútur. Í heimsóknunum verður öndun, blóðþrýstingur, hæð og þyngd mæld . Ekki verður greitt fyrir þátttöku en mælingarnar verður þáttakendum að kostnaðarlausu.

Áhætta og ávinningu r: Áhætta af þátttöku er engin en ávinningur er að niðurstöður rannsóknarinnar geta verið gagnlegar fyrir bættan skilning á astmasjúkdómnum. Rannsóknin er unnin með samþykki Vísindasiðanefndar og hefur verið tilkynnt til Persónuverndar. Aðgengi að rannsóknargögnum : Allar upplýsingar sem þátttakendur veita í rannsókninni, verða meðhöndlaðar samkvæmt ströngustu reglum um trúnað og nafnleynd og farið að íslenskum lögum varðandi persónuvernd, vinnslu og eyðingu frumgagna. Í tölfræðilegum úrvinnsluskrám koma ekki fram nöfn og kennitölur þátttakenda heldur fær hver og einn sitt númer sem ábyrgðamaður heldur einn skrá yfir. Rannsóknargögn verða varðveitt á öruggum stað hjá ábyrgðarmanni á meðan á rannsókn stendur og öllum gögnum verði eytt að rannsókn lokinni.

Þér er ekki skylt að taka þátt í rannsókninni og þú getur hætt við þátttöku hvenær sem er, án frekari útskýringa. Afstaða þín mun ekki hafa áhrif á þá þjónustu heilbrigðiskerfisins sem þú kannt að þurfa í framtíðinni

Frekari upplýsingar: Ef þú hefur áhuga að taka þátt í rannsókninni eða fá frekari upplýsingar, vinsamlegast hafðu samband við Monique van Oosten í síma 8998456 eða með tölvupósti: monique@centrum

Með von um góðar undirtektir, Marta Guðjónsdóttir, lektor og ábyrgðarmaður rannsóknarinnar. Monique van Oosten, sjúkraþjálfari, Buteykoþjálfari og meistaranemi í lýðheilsuvísindum.

______

Ef þú hefur spurningar um rétt þinn sem þátttakandi í vísindarannsókn eða vilt hætta þátttöku í rannsókninni getur þú snúið þér til Vísindasiðanefndar, Hafnarhúsinu, Tryggvagötu 17, 101Reykjavík. Sími: 551-7100, fax: 551-1444, tölvupóstfang: [email protected].

Appendix D

Mat á astmastjórn (ACT TM )

Sjúklinganúmer:______

Dagsetning:______

Eftirfarandi mat getur auðveldað fólki með astma (12 ára og eldra) að meta astmastjórn sína. Alls eru FIMM spurningar. Dragðu hring um svarið þitt við hverri spurningu. Svaraðu eins hreinskilningslega og hægt er. Þú færð heildarniðurstöðu úr mati þínu á astmastjórnun með því að leggja saman stigin þín fyrir hvert svar. 1. Síðastliðnar 4 vikur , hversu oft kom astminn í veg fyrir að þú kæmir jafn miklu í verk í vinnu, skóla eða heima?

1) alltaf 2) oftast 3) stundum 4) sjaldan 5) aldrei

2. Síðastliðnar 4 vikur , hve oft hefurðu fundið fyrir mæði?

1) Oftar en einu sinni á dag 2) Einu sinni á dag 3) 3 til 6 sinnum í viku 4) Einu sinnu til tvisvar í viku 5) Alls ekki

3. Síðastliðnar 4 vikur , hversu oft vaknaðir þú um nótt eða fyrr en vanalega að morgni vegna einkenna astmans (blásturshljóðs í lungum, hósta, mæði, þrengsla eða verkjar fyrir brjósti)?

1) 4 eða fleiri nætur í viku

2) 2 til 3 nætur í viku 3) Einu sinni í viku 4) Einu sinni eða tvisvar 5) Alls ekki

4. Síðastliðnar 4 vikur , hversu oft hefurðu notað neyðarúðann þinn eða innúðalyf (eins og Ventolin®, Bricanyl® eða Salbutamol NM Pharma®)?

1) 3 eða oftar á dag 2) 1 sinni eða 2 á dag 3) 2 sinnum eða 3 í viku 4) Einu sinni í viku eða sjáldnar 5) Alls ekki

5. Hvaða einkunn myndirðu gefa astma stjórn þinni síðastliðnar 4 vikur? 1) Alls engin stjórn 2) Léleg stjórn 3) Nokkur stjórn 4) Góð stjórn 5) Algjör stjórn Leggðu nú saman stigin þín.

Samtals :______stig.

Stig: 25 – Til hamingju. Þú hefur haft algera stjórn á astmanum síðastliðnar 4 vikur. Þú hefur engin einkenni haft og astminn hefur ekkert hamlað þér. Leitaðu til læknis eða hjúkrunarfræðings ef það breytist.

Stig: 20-24 – Á réttri leið. Astmanum hefur e.t.v. verið STJÓRNAÐ VEL, síðastliðnar 4 vikur, en ekki STJÓRNAÐ ALGERLEGA. Læknir eða hjúkrunarfræðingur gæti hjálpað þér að stefna að ALGERRI STJÓRN.

Stig: færri en 20 – Ekki á réttri leið. Astmanum hefur e.t.v. EKKI VERIÐ STJÓRNAÐ síðastliðnar 4 vikur. Læknir eða hjúkrunarfræðingur getur mælt með aðgerðaráætlun til að takast á við astmann svo þú náir betri stjórn á honum.

Notað með leyfi GSK á Íslandi.

Appendix E ASTMA DAGBÓK

Þessi astma dagbók getur hjálpað okkur að halda utan um þína astmastjórnun. ‹ Skráðu sjúklingsnúmer og mánuð.

‹ Einkenni: Notaðu dagbókina til að skrá ef breyting er á einkennum þínum; Skráðu alvarleika: 1 = væg; 2 = meðallagi; 3 = alvarleg.

‹ Ofnæmisvakar : Skráðu og krossaðu við þegar þú hefur komið í snertingu við einn af mögulegum ofnæmisvökum þínum (t.d. gæludýr, reykingar, frjókorn o.s.frv.).

‹ Lyfjanotkun: Skráðu og krossaðu við þegar þú hefur tekið neyðarlyf. Skráðu og krossaðu einnig við þegar breyting er á lyfjanotkun sem þú tekur að staðaldri.

‹ Breath holding time: Þessi mæling byrjar þú að skrá þegar þú ert byrjaður/-uð að æfa samkvæmt öndunarmeðerðinni.

‹ Astma control test. Þetta fyllir þú út á sama tíma einu sinni á mánuði. Hér áttu að skrá tölustafi samkvæmt ACT leiðbeininum.

Appendix F